Cannabinoid chewing gum with high intensity sweeteners

ABSTRACT

The present invention relates cannabinoid chewing gums with improved flavor perception. The cannabinoid chewing gums include water-soluble chewing gum ingredients and water-insoluble gum base, one or more cannabinoids with an off-note taste, one or more high intensity sweeteners in an amount of 0.05 to 0.9% by weight of the cannabinoid chewing gum that partly serves to mask the taste of said unbound cannabinoids, one or more flavoring ingredients in an amount of 0.01 to 5% by weight of the cannabinoid chewing gum that in combination with the one or more high intensity sweeteners partly serves to mask the taste of said unbound cannabinoids, wherein the one or more cannabinoids is located in close proximity with the one or more high intensity sweeteners as well as the one or more flavoring ingredients.

FIELD OF THE INVENTION

The invention relates to the field of cannabinoids and alleviation ortreatment of a condition with one or more cannabinoids. In particular,the invention relates to chewing gum as a vehicle for mucosal deliveryof one or more cannabinoids.

BACKGROUND OF THE INVENTION

In general, only very limited attention is given in the prior art to theimpact of chewing gum base and components in such gum base for releaseproperties of cannabinoids. Also, less attention is addressed to theimpact of gum base and components in such gum base for sensoryproperties of chewing gum with cannabinoids. Here, important sensoryproperties include initial chew, texture, flavor perception, sweetnessperception and off-notes associated with cannabinoids. These propertiesare both relevant from a convenience perspective in chewing gum, butcertainly also in order to support an appropriate delivery ofcannabinoids from chewing gum and avoid adverse side effects ofcannabinoids.

Cannabinoids are known for their health improving properties and havebeen used with respect to various medical purposes in the past. Amongthese medical purposes, cannabinoids have in particular been used foralleviating or treating different kinds of pain and counteracting sideeffects in relation to cancer treatment, such as nausea.

One way of administering cannabinoids revealed in the prior art is byinhalation or smoking. A problem related to such administration is thatrapid blood absorption via the lungs may be undesirable. Smoking may notonly have certain side effects, but the administration of cannabinoidsmay also be difficult to manage with respect to safety.

WO 2009/120080 discloses the use of chewing gum as a medical carrier andrelease vehicle of cannabinoids. The chewing gum disclosed herein mayfacilitate prolonged release of cannabinoids compared to other types ofadministering methods. However, various problems and challenges areassociated with the chewing gum disclosed, partly based on the specificproperties of cannabinoids. While certain specific conventional gumbases are used in formulating the chewing gum disclosed, the gum basesappear to have drawbacks for use in combination with cannabinoids.

One of the challenges with chewing gum as a delivery vehicle ofcannabinoids is that cannabinoids tend to be associated with off-notesduring administration due to the specific physiochemical properties ofthe compounds. The taste masking challenge is more profound when ahigher release of cannabinoids are delivered by such chewing gum. Ifoff-notes are the predominant sensation during administration,convenience may be affected and even more critically, the delivery ofcannabinoids may also be affected. Saliva production may be suppressed,and the delivery vehicle may not be handled correctly.

Hence, there is a need in the prior art for improved chewing gumformulations that solve the above-referenced challenges and problems ofthe prior art. In particular, there is a need in the prior art for newgum base formulations for use in chewing gum that support appropriatedelivery of cannabinoids combined with beneficial sensory properties,such as flavor perception, sweetness perception and off-notes.

SUMMARY OF THE INVENTION

Accordingly, there is provided a chewing gum for mucosal delivery ofcannabinoids, the chewing gum comprising water-soluble chewing gumingredients and water-insoluble gum base, wherein the gum basecomprising one or more natural resins in an amount of 10-40% by weightof the gum base, one or more elastomers in an amount of 3-30% by weightof the gum base, and one or more elastomer plasticizers in an amount of8-50% by weight of the gum base, and wherein the chewing gum comprisingone or more high intensity sweeteners in an amount of 0.01 to 1% byweight of the chewing gum, and wherein the chewing gum comprises one ormore cannabinoids.

The present invention may solve various problems of the prior art andaims at establishing a chewing gum that combines beneficial deliveryproperties of cannabinoids combined with advantageous sensoryproperties.

A very important aspect of the present invention is the provision ofbeneficial sensory properties. Here, important sensory propertiesinclude initial chew, texture, flavor perception, sweetness perceptionand off-notes associated with cannabinoids. These properties are bothrelevant from a convenience perspective in chewing gum, but certainlyalso in order to support an appropriate delivery of cannabinoids fromchewing gum, such as an improved release profile, and avoid adverse sideeffects of cannabinoids.

The present inventors have shown very surprising results with thespecific combination of features of the present invention in terms ofthese sensory properties. It was an unexpected result that the inventioncould both contribute to an improved release profile, such as rapidrelease of cannabinoids, and at the same time provide very beneficialsensory properties which in terms may also support an appropriatedelivery of cannabinoids from chewing gum and avoid adverse side effectsof cannabinoids.

The taste masking challenge is more profound when a higher release ofcannabinoids are delivered by such chewing gum. If off-notes are thepredominant sensation during administration, convenience may be affectedand even more critically, the delivery of cannabinoids may also beaffected. Saliva production may be suppressed, and the delivery vehiclemay not be handled correctly.

In particular, the one or more high intensity sweeteners of the presentinvention in the specified amount may be advantageous according to theinvention. It was seen that this amount in combination with the featuresof the invention serves to of particular interest in terms of limitingoff-notes from the one or more cannabinoids of the invention.

With respect to release properties, the present invention may offer animproved release profile of cannabinoids compared to conventional gumbase. In particular, the specific gum base formulation of the presentinvention may serve to provide improved release characteristics ofcannabinoids compared to conventional gum base applied in combinationwith cannabinoids.

In the present context, an improved release profile may refer to ahigher release of cannabinoids which is particularly seen as anadvantage since it has traditionally been a challenge with release ofcannabinoids from chewing gum. In order to obtain beneficial healtheffects both in terms of systemic delivery of cannabinoids as well aslocal delivery of cannabinoids, it is required that a certain content ofcannabinoids are released over time. Hence, rapid release ofcannabinoids may be an advantage of the present invention.

In addition, the present invention may serve to provide controlledrelease of cannabinoids such that the chewing gum is tailored to deliveran effective content of cannabinoids over time and at the same timeavoid adverse effects of cannabinoids, such as off-notes. Accordingly,the chewing gum of the present invention may at the same time offer arelatively sustained release of cannabinoids.

The special combination of the present invention with one or morenatural resins in a certain amount combined with one or more elastomerplasticizers in a certain amount is particularly advantageous forrelease characteristics of cannabinoids. It was unexpected to thepresent inventors that the combination according to the invention wouldcontribute to improved release characteristics of cannabinoids.Importantly, the elastomer plasticizer in the present context serves toplasticize the elastomers present in the gum base. The elastomerplasticizers are not to be considered elastomers by themselves in thepresent context. The elastomeric properties are provided by theelastomers of the invention, and the elastomer plasticizers are presentto plasticize the elastomers in order to obtain the beneficial releasecharacteristics of the present invention.

One of the sensory properties that are particularly advantageous is theinitial chew. Both in order to secure a desired release of cannabinoidsand to improve the sensation by a consumer, it is critical that theinitial chew is improved. Also, the texture of the chewing gum duringchewing is critical for the release of cannabinoids and the experienceas well as convenience during chewing. These properties may be improvedby the present invention which was not expected by the inventors of thepresent invention.

The present gum base may also offer improved taste masking in the sensethat the gap between the release of the cannabinoid and the tastemasking ingredients may be overall reduced.

Another important result of the specific combination of cannabinoids andgum base composition is that a reduced content of cannabinoids willreduce the requirements for taste masking, or alternatively make thetaste masking more efficient. This is important given the fact that whenapplied as a medical delivery platform, many patients may havedifficulties in sensing the taste of cannabinoid.

It should also be noted that this unexpected effect is very attractivein relation to medicated chewing gum in the present context as a largegroup of the patients who may benefit from the inventive chewing gumwill be very vulnerable to off-notes.

In an embodiment of the invention, the chewing gum comprising one ormore high intensity sweeteners in an amount of 0.05 to 0.9% by weight ofthe chewing gum.

A preferred embodiment of the invention is when the chewing gumcomprises one or more high intensity sweeteners in an amount of 0.05 to0.9% by weight of the chewing gum.

In particular with respect to sweetness, the ranges of the invention mayprovide an advantage in terms of sensory properties compared to theprior art. Also, with respect to flavors perception, the ranges providecertain benefits. It is noted that the sensory properties and benefitsare closely related to the specific gum base composition of the presentinvention.

The gum base formulation may influence the release of cannabinoids, suchas providing a rapid release of cannabinoids, and the resultingoff-notes may in turn be counteracted by the specific content ofhigh-intensity sweeteners of the present invention. Hence, the sensoryproperties should be seen in combination with the remaining vehicleprovided by the invention.

Accordingly, the technical effect of the invention may be seen as acombined effect of improved sensory properties and improved releasedelivery characteristics. One such sensory property may be sweetness orit may be flavor perception. It may also be a combination of suchtechnical properties. Additionally, the technical properties may bereduced off-notes of the chewing gum of the present invention.

In an embodiment of the invention, the chewing gum comprising one ormore high intensity sweeteners in an amount of 0.05 to 0.8% by weight ofthe chewing gum.

In an embodiment of the invention, the chewing gum comprising one ormore high intensity sweeteners in an amount of 0.1 to 0.8% by weight ofthe chewing gum.

In an embodiment of the invention, at least 10% by weight of the one ormore cannabinoids are present in unbound form.

Within the limits of the present invention, a certain content ofcannabinoids may be present in bound form as long as a certain amountwill also be present in unbound form.

In an embodiment of the invention, the one or more cannabinoids aremixed into the water-insoluble gum base in unbound form.

A particular advantage may be seen when the cannabinoids are present inunbound form. By “unbound form” is meant that the cannabinoids are notbound to any carrier material that limits free transfer and release ofthe cannabinoids in the chewing gum formulation. An example of “boundform” is if the cannabinoids are part of a plant material and thecannabinoids are not extracted and separated from the plant material.Other examples may be a pre-blend of microcrystalline cellulose whichwas seen by the inventors to limit free transfer of cannabinoids in thechewing gum formulation. Also, in some embodiments, other pre-blendswith water-insoluble carrier is to be avoided due to both problems withsensation appearance and release of cannabinoids.

The advantage of having the cannabinoids in free form may also beimproved sensory characteristics. For instance, plant material maycompromise the chewing gum matrix and for instance microcrystallinecellulose may impact the texture of the chewing gum and the complexmatrix of chewing gum in general.

In an embodiment of the invention, at least 90% by weight of the one ormore cannabinoids are present in unbound form.

The advantage of having the cannabinoids in free form may also beimproved sensory characteristics. For instance, plant material maycompromise the chewing gum matrix and for instance microcrystallinecellulose may impact the texture of the chewing gum and the complexmatrix of chewing gum in general.

In an embodiment of the invention, the one or more cannabinoids arehomogeneously distributed with the one or more high intensitysweeteners.

By distributing the one or more cannabinoids homogeneously with the oneor more high intensity sweeteners, it may be secured that maximal effectis achieved with respect to taste masking of the cannabinoids.

One of the great advantages of the homogeneous distribution may be toobtain a matrix that has a high content uniformity, i.e. the productpossesses characteristics with a uniform distribution of cannabinoidsand high intensity-sweeteners.

When the one or more cannabinoids are homogeneously distributed with theone or more high intensity sweeteners, it would be expected that therelease and sensory characteristics would be compromised. To theopposite, it was seen that the sensory characteristics were improved andto the surprise of the inventors, it was also seen that an improvedrelease may be obtained.

In an embodiment of the invention, the one or more cannabinoids arelocated in close proximity with the one or more high intensitysweeteners.

Traditionally, water-insoluble gum base is seen as a matrix that doesnot offer a high degree of release of cannabinoids. In particular, withrespect to cannabinoids, it is a surprise that improved release may beseen when the one or more cannabinoids are located in close proximitywith the one or more high intensity sweeteners.

It would not have been expected that cannabinoids in close associationwith the one or more high intensity sweeteners would release to thedegree as seen by the inventors of the present invention.

In an embodiment of the invention, the water-soluble chewing gumingredients and water-insoluble gum base are partly separated in thechewing gum.

In certain embodiments of the invention, partly separating thewater-soluble chewing gum ingredients from the water-insoluble gum basein the chewing gum may provide some advantages. For instance, therelease may be controlled to a higher degree and the release may bemodulated to a higher degree.

One example of such a configuration is where a coating is provided tothe chewing gum. In this case, an amount of water-soluble ingredientsmay be present in the coating and water-insoluble ingredients may belocated as a core within the coating. By this configuration,advantageous controlled release properties may be provided.

Another example of such a configuration is where the water-solublechewing gum ingredients and water-insoluble gum base are partlyseparated within the chewing gum, excluding the coating. This may occurwhen the water-soluble chewing gum ingredients and water-insoluble gumbase are not completely homogeneous. However, this may also occur whenthe water-soluble chewing gum ingredients and water-insoluble gum baseare partly divided within the chewing gum. Certain beneficial releaseproperties and sensory properties may be associated with such aconfiguration.

In an embodiment of the invention, the water-soluble chewing gumingredients are partly located in discrete areas of the chewing gum.

While a homogeneous matrix of the chewing gum is preferred in someembodiments of the invention, in other embodiments of the invention itis preferred with discrete areas of water-soluble ingredients within thechewing gum. If for instance discrete areas are provided within thechewing gum, the release characteristics may be improved, or it may beeasier to control the release from the chewing gum. While discrete areasof water-insoluble ingredients may be a benefit for extruded chewinggum, discrete areas may also be a benefit for other categories ofchewing gum, such as chewing gum that is not extruded with a coherentchewing gum mass.

In an embodiment of the invention, the water-soluble chewing gumingredients are partly located in one layer of the chewing gum and thewater-insoluble gum base is partly located in another layer of thechewing gum.

In certain embodiments of the invention, partly separating thewater-soluble chewing gum ingredients in one layer from thewater-insoluble gum base in another layer of the chewing gum may providesome advantages. For instance, the release may be controlled to a higherdegree and the release may be modulated to a higher degree.

One example of such a configuration is where a coating is provided tothe chewing gum. In this case, an amount of water-soluble ingredientsmay be present in the coating and water-insoluble ingredients may belocated as a core within the coating. By this configuration,advantageous controlled release properties may be provided.

Another example of such a configuration is where the water-solublechewing gum ingredients and water-insoluble gum base are partlyseparated in one or more layers within the chewing gum, excluding thecoating. This may be configured to be two layers separated from eachother, such as two distinct modules cohered together with one facingsurface and additional surfaces that are not cohered together. In such aconfiguration, both layers may comprise water-insoluble chewing gumingredients and water-soluble ingredients. In the alternative, only onelayer may comprise water-insoluble chewing gum ingredients and bothlayers water-soluble ingredients.

In an embodiment of the invention, the water-soluble chewing gumingredients are partly located in one layer of the chewing gum and thewater-insoluble gum base is located in another layer of the chewing gum.

In a particularly preferred embodiment, only one layer compriseswater-insoluble chewing gum ingredients and both layers water-solubleingredients. This may be configured to be two layers separated from eachother, such as two distinct modules cohered together with one facingsurface and additional surfaces that are not cohered together. Incertain embodiments, one layer consist of water-soluble chewing gumingredients. In certain other embodiments, one layer substantiallyconsist of water-soluble chewing gum ingredients and another layercontain water-insoluble chewing gum ingredients. Certain beneficialrelease properties and sensory properties may be associated with such aconfiguration.

In an embodiment of the invention, the water-soluble chewing gumingredients are partly located in one layer of the chewing gum andpartly in another layer of the chewing gum.

In a further preferred embodiment, one layer comprises water-solublechewing gum ingredients and another layer comprises water-solubleingredients. This may be configured to be two layers separated from eachother, such as two distinct modules cohered together with one facingsurface and additional surfaces that are not cohered together. Incertain embodiments, one layer consists of water-soluble chewing gumingredients. In certain other embodiments, one layer substantiallyconsist of water-soluble chewing gum ingredients and another layercontain water-insoluble chewing gum ingredients. Certain beneficialrelease properties and sensory properties may be associated with such aconfiguration.

In an embodiment of the invention, the one or more cannabinoids are partof the water-soluble chewing gum ingredients.

In certain embodiments, it is an advantage that the one or morecannabinoids are part of the water-soluble chewing gum ingredients bothrespect to increased release of the one or more cannabinoids and withrespect to sensory properties.

In an embodiment of the invention, the one or more high intensitysweeteners are part of the water-soluble chewing gum ingredients.

In certain embodiments, it is an advantage that the one or more highintensity sweeteners are part of the water-soluble chewing gumingredients both respect to increased release of the high intensitysweeteners and with respect to sensory properties.

In an embodiment of the invention, the water-soluble chewing gumingredients are mixed into the water-insoluble gum base.

While different categories of chewing gum is within the scope of thepresent invention, such as those described above, in certain embodimentsit is preferred that the water-soluble chewing gum ingredients are mixedinto the water-insoluble gum base. An example of such a configuration isextruded chewing gum, where a coherent mass of chewing gum is providedas the delivery vehicle. In this sense, “mixed into” is to be understoodas providing a homogeneous mass of chewing gum.

In an embodiment of the invention, the one or more high intensitysweeteners are homogeneously distributed in the water-insoluble gumbase.

By distributing the one or more high intensity sweeteners homogeneouslyin the water-insoluble gum base, it may be secured that maximal effectis achieved with respect to release of the cannabinoids. Furthermore, itwould not have been expected that high intensity sweeteners in closeassociation with the water-insoluble gum base would release to thedegree as seen by the inventors of the present invention.

Traditionally, water-insoluble gum base is seen as a matrix that doesnot offer a high degree of release of cannabinoids. In particular, withrespect to high intensity sweeteners, it is a surprise that improvedrelease may be seen when elastomer plasticizers are applied in the gumbase. This is even more surprising when the high intensity sweetenersare homogeneously distributed in close proximity with the elastomerplasticizers.

In an embodiment of the invention, the one or more high intensitysweeteners are embedded in the water-insoluble gum base.

One of the great advantages of embedding the high intensity sweetenersin the water-insoluble gum base comprising the one or more elastomerplasticizers may be to obtain a matrix that has a high contentuniformity, i.e. the product possesses characteristics with a uniformdistribution of high intensity sweeteners.

When the high intensity sweeteners are embedded in the water-insolublegum base, it would be expected that the release and sensorycharacteristics would be compromised. To the opposite, it was seen thatthe sensory characteristics were improved and to the surprise of theinventors, it was also seen that an improved release may be obtained.Certainly, since the water-insoluble gum base comprise elastomerplasticizers, it would be expected that the release of high intensitysweeteners would be lower.

In an embodiment of the invention, the one or more cannabinoids arehomogeneously distributed in the water-insoluble gum base.

By distributing the one or more cannabinoids homogeneously in thewater-insoluble gum base comprising the one or more elastomerplasticizers, it may be secured that maximal effect is achieved withrespect to release of the cannabinoids. Furthermore, it would not havebeen expected that cannabinoids in close association with thewater-insoluble gum base would release to the degree as seen by theinventors of the present invention.

Traditionally, water-insoluble gum base is seen as a matrix that doesnot offer a high degree of release of cannabinoids. In particular, withrespect to cannabinoids, it is a surprise that improved release may beseen when elastomer plasticizers are applied in the gum base. This iseven more surprising when the cannabinoids are homogeneously distributedin close proximity with the elastomer plasticizers.

In an embodiment of the invention, the one or more cannabinoids areembedded in the water-insoluble gum base.

One of the great advantages of embedding the cannabinoids in thewater-insoluble gum base comprising the one or more elastomerplasticizers may be to obtain a matrix that has a high contentuniformity, i.e. the product possesses characteristics with a uniformdistribution of cannabinoids.

When the cannabinoids are embedded in the water-insoluble gum base, itwould be expected that the release and sensory characteristics would becompromised. To the opposite, it was seen that the sensorycharacteristics were improved and to the surprise of the inventors, itwas also seen that an improved release may be obtained. Certainly, sincethe water-insoluble gum base comprise elastomer plasticizers, it wouldbe expected that the release of cannabinoids would be lower.

In an embodiment of the invention, the chewing gum is formulated as anextruded chewing gum, wherein the water-soluble chewing gum ingredientsare mixed into the water-insoluble gum base.

In an embodiment of the invention, the taste of the one or morecannabinoids is partly masked by the one or more high intensitysweeteners.

In an embodiment of the invention, the taste of the one or morecannabinoids is partly masked by the one or more high intensitysweeteners in combination with one of more flavors.

In an embodiment of the invention, the release rate of the one or morecannabinoids is at least 10% by weight of the one or more cannabinoidswithin the first 5 minutes upon oral administration.

In certain product formulations, such as formulations where systemiceffects are to be achieved relatively quickly, it is advantageous thatthe release profile is high. In the present context, a release rate ofmore than 10% is considered to be relatively high. Due to the specificproperties of cannabinoids, a release rate of more than 10% isconsidered to be high. The inventors of the present invention did notexpect that such a release rate could be obtained according to theinvention. It was expected that the specific composition of the gum basewould not allow such a high release rate.

In certain embodiments of the invention, the release rate is higher than10% within the first 5 minutes upon oral administration, such as 20% or30%. In this context the release rate is measured from the time that thechewing gum is inserted in the mouth and the initial chew is effectuatedand chewing is commenced with a suitable chewing gum rate, such as 1chew pr. second, until 5 minutes of chewing.

Importantly, the improved sensory characteristics of the chewing gum ofthe invention also accommodates an improved release rate ofcannabinoids. The reason may be attributed to the fact that if theinitial chew is improved and the chewing gum texture is also improved,this would trigger the user to effectively chew the product. Also, theproduction of saliva may be enhanced once the product formulation isimproved, which in turn may accommodate further increased release ofcannabinoids. However, the precise mechanism is not well understood.

In an embodiment of the invention, the release rate of the one or morehigh intensity sweeteners is about the same as the release rate of theone or more cannabinoids upon oral administration.

In an embodiment of the invention, the release rate of the one or morehigh intensity sweeteners is at least 10% by weight of the highintensity sweeteners within the first 5 minutes upon oraladministration.

In certain product formulations, such as formulations where systemiceffects are to be achieved relatively quickly, it is advantageous thatthe release profile is high. In the present context, a release rate ofmore than 10% is considered to be relatively high. Due to the specificproperties of high intensity sweeteners, a release rate of more than 10%is considered to be high. The inventors of the present invention did notexpect that such a release rate could be obtained according to theinvention. It was expected that the specific composition of the gum basewould not allow such a high release rate.

In certain embodiments of the invention, the release rate is higher than10% within the first 5 minutes upon oral administration, such as 20% or30%. In this context the release rate is measured from the time that thechewing gum is inserted in the mouth and the initial chew is effectuatedand chewing is commenced with a suitable chewing gum rate, such as 1chew pr. second, until 5 minutes of chewing.

Importantly, the improved sensory characteristics of the chewing gum ofthe invention also accommodates an improved release rate of highintensity sweeteners. The reason may be attributed to the fact that ifthe initial chew is improved and the chewing gum texture is alsoimproved, this would trigger the user to effectively chew the product.Also, the production of saliva may be enhanced once the productformulation is improved, which in turn may accommodate further increasedrelease of high intensity sweeteners. However, the precise mechanism isnot well understood.

In an embodiment of the invention, the one or more high intensitysweeteners are selected from the group consisting of sucralose,aspartame, salts of acesulfame, alitame, saccharin and its salts,cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin,monellin, neotame, advantame, monk fruit extract, stevioside and thelike, alone or in combination.

In an embodiment of the invention, the one or more high intensitysweeteners are selected from the group consisting of sucralose,aspartame, stevioside, salts of acesulfame, alone or in combination.

In an embodiment of the invention, the one or more high intensitysweeteners are homogeneously distributed in the water-soluble chewinggum ingredients.

In an embodiment of the invention, the water-soluble chewing gumingredients comprise at least one sugar alcohol.

Best results were seen when the water-soluble chewing gum ingredientscomprised at least one sugar alcohol. Both with respect to releaseproperties and sensory properties, the chewing gum was improved when atleast one sugar alcohol was present in the formulation.

In an embodiment of the invention, the water-soluble chewing gumingredients comprise at least one saccharose.

In an embodiment of the invention, the one or more cannabinoids arehomogeneously distributed in the one or more sugar alcohols orsaccharose.

In an embodiment of the invention, the chewing gum compriseswater-soluble chewing gum ingredients in an amount of 40-70% by weightof the chewing gum.

It is particularly preferred that the water-soluble chewing gumingredients are present in an amount of 40-70% by weight of the chewinggum. This range of water-soluble chewing gum ingredients have shownparticularly beneficial results. The inventors of the present inventiondid not expect that an improved release would be possible within thisrange of water-soluble chewing gum ingredients. As the water-solublechewing gum ingredients are mixed into the gum base during themanufacturing process, it was expected the water-soluble ingredients didnot provide enough porosity of the chewing gum to facilitate an improvedrelease. In addition, due to the specific properties of cannabinoids, itwas a surprise to discover that the release rate of cannabinoids wasimproved with water-soluble chewing gum ingredients.

Importantly, the sensory characteristics were thought to be compromisedwhen the water-soluble chewing gum ingredients are present in an amountof 40-70% by weight of the chewing gum. However, contrary toexpectations, the sensory properties were improved in combination withan improved release of cannabinoids. In particular, the texture of thechewing gum was improved. It was expected that the texture would beworse with this amount of water-soluble ingredients in the chewing gum.

In an embodiment of the invention, the gum base comprises less than 50%by weight of gum base polymers.

In order to achieve the effects of the invention, it may in someembodiments be preferred that the content of polymers is relatively low.This ensures for instance that the release of cannabinoids may beimproved and that the sensory properties of the chewing gum may beimproved. In particular, when vinyl laurate-vinyl acetate copolymer areapplied, it appears critical that the content of gum base polymersshould be below 50% by weight of the gum base. It appears that thispolymer may compromise the chewing gum formulation in the presentcontext.

In an embodiment of the invention, the one or more elastomerplasticizers comprise one or more polyvinyl acetate elastomerplasticizers.

A significant advantage of the present invention is obtained when theone or more elastomer plasticizers comprise one or more polyvinylacetate elastomer plasticizers in a certain amount. Surprisingly, therelease characteristics of the cannabinoids were seen to be particularlyimproved with these plasticizers. The polyvinyl acetate elastomerplasticizers are not to be considered elastomers by themselves in thepresent context. Hence, the molecular weight and other polymerproperties are tailored for the polyvinyl acetate elastomer plasticizersto work as plasticizers. The elastomeric properties are provided by theelastomers of the present invention and the polyvinyl acetate elastomerplasticizers are present to plasticize the elastomers in order to obtainthe beneficial release characteristics of the present invention.Polyvinyl acetate elastomers are not to be considered polyvinyl acetateelastomer plasticizers.

In an embodiment of the invention, the one or more polyvinyl acetateelastomer plasticizers are present in an amount of 15-35% by weight ofthe gum base.

A particularly preferred range of polyvinyl acetate elastomerplasticizers is 15-35% by weight of the gum base. Here, veryadvantageous results were achieved with respect to release ofcannabinoids and sensory characteristics, such as initial chew, texture,flavor perception, sweetness and off-notes. That the preferred rangewould be on a level such high was a surprise to the inventors. Also, itwas not expected that such high amount of polyvinyl acetate elastomerplasticizers would have a combined effect of improved sensoryproperties.

In other embodiments of the invention, the one or more polyvinyl acetateelastomer plasticizers are present in an amount of 17-33% by weight ofthe gum base. In other embodiments of the invention, the one or morepolyvinyl acetate elastomer plasticizers are present in an amount of20-35% by weight of the gum base. In other embodiments of the invention,the one or more polyvinyl acetate elastomer plasticizers are present inan amount of 20-30% by weight of the gum base. In other embodiments ofthe invention, the one or more polyvinyl acetate elastomer plasticizersare present in an amount of 15-40% by weight of the gum base. In otherembodiments of the invention, the one or more polyvinyl acetateelastomer plasticizers are present in an amount of 20-40% by weight ofthe gum base.

In an embodiment of the invention, the gum base does not comprise vinyllaurate-vinyl acetate copolymer.

To the surprise of the inventors, it was seen that vinyl laurate-vinylacetate copolymer may compromise the release of cannabinoids and thesensory characteristics of the chewing gum. Hence, it is preferred thatthis copolymer is not present in the gum base.

In certain other embodiments, the gum base polymers comprise less than20% by weight of vinyl laurate-vinyl acetate copolymer. In certain otherembodiments, the gum base polymers comprise less than 15% by weight ofvinyl laurate-vinyl acetate copolymer. In certain other embodiments, thegum base polymers comprise less than 10% by weight of vinyllaurate-vinyl acetate copolymer. In certain other embodiments, the gumbase polymers comprise less than 5% by weight of vinyl laurate-vinylacetate copolymer.

In some embodiments of the invention, if polyvinyl acetate elastomersare present in the gum base formulation, the gum base polymers compriseless than 20% by weight of vinyl laurate-vinyl acetate copolymer, suchas less than 10%, such as less than 5%. In the present context,polyvinyl acetate elastomers are not the same as polyvinyl acetateelastomer plasticizers. Basically, polyvinyl acetate elastomers provideselastomeric properties to the chewing gum, whereas polyvinyl acetateelastomer plasticizers work to plasticize the elastomers present in thegum base.

In an embodiment of the invention, the one or more natural resins arepresent in an amount of 15-35% by weight of the gum base.

The natural resins provides beneficial properties to the presentinvention. In particular the combination of natural resins and elastomerplasticizers provides beneficial properties to the gum base andfollowingly to the chewing gum formulation in general, both in terms ofrelease properties of cannabinoids and sensory properties.

A particularly advantageous range of natural resins is 15-35% by weightof the gum base. This range of natural resin was seen to give animproved release profile and best sensory properties. While naturalresins of 10-40% by weight of gum base is also within the scope of theinvention, the best results were seen with 15-35% by weight of the gumbase.

In other embodiments of the invention, the one or more natural resinsare present in an amount of 17-33% by weight of the gum base. In otherembodiments of the invention, the one or more natural resins are presentin an amount of 20-35% by weight of the gum base. In other embodimentsof the invention, the one or more natural resins are present in anamount of 20-30% by weight of the gum base. In other embodiments of theinvention, the one or more natural resins are present in an amount of15-40% by weight of the gum base. In other embodiments of the invention,the one or more natural resins are present in an amount of 20-40% byweight of the gum base.

In an embodiment of the invention, the one or more natural resins areselected from the group consisting of polyterpene resins, resins basedon gum rosin, wood rosin or tall oil resin.

In an embodiment of the invention, the one or more elastomers areselected from the group consisting of styrene-butadiene copolymers,polyisobutylene, isobutylene-isoprene copolymers, polyethylene,polyurethane or any combination thereof.

In an embodiment of the invention, the one or more elastomers arepresent in an amount of 3-20% by weight, such as in an amount of 3-15%by weight, such as in an amount of 5-10% by weight.

In an embodiment of the invention, at least a part of the water-solublechewing gum ingredients is mixed into the water-insoluble gum base priorto mixing the one or more cannabinoids into the water-insoluble gumbase.

In the present context, a premixture is mainly used to allocate the oneor more cannabinoids properly to the manufacturing process and securethat the uniformity is not compromised and that the cannabinoids aredistributed properly into the mixture. Preferably, the cannabinoids areprovided in a premixture with one or more sugar alcohols. It was asurprise to the inventors that a premixture was important to have thecannabinoids distributed properly in the manufacturing process and toend up with a product where the uniformity was consistent.

In an embodiment of the invention, the one or more cannabinoids arepresent in an amount of 0.1 to 200 mg. In some other embodiments of theinvention, the one or more cannabinoids are present in an amount of 0.1to 100 mg. In some other embodiments of the invention, the one or morecannabinoids are present in an amount of 0.1 to 50 mg. In an embodimentof the invention said chewing gum comprises said cannabinoids in anamount of 0.1-30 mg, such as 1-20 mg, such as 5-15 mg.

In an embodiment of the invention, the one or more cannabinoids are notpart of a pre-mixture with microcrystalline cellulose.

In certain embodiments of the invention, the cannabinoids are not partof a pre-mixture with microcrystalline cellulose. It was seen that bothrelease rate of cannabinoids and sensory properties were to some degreecompromised by using microcrystalline cellulose in premixture. Withoutbeing bound by theory, it is expected that cannabinoids are bound to ahigher degree to microcrystalline cellulose than preferred.

In some embodiments, less than 50% of the cannabinoids are part of apre-mixture with microcrystalline cellulose. In some embodiments, lessthan 20% of the cannabinoids are part of a pre-mixture withmicrocrystalline cellulose. In some embodiments, less than 10% of thecannabinoids are part of a pre-mixture with microcrystalline cellulose.

In an embodiment of the invention, the one or more cannabinoids comprisecannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV),salts and derivatives thereof. In an embodiment of the invention the oneor more cannabinoids comprises CBD, salts and derivatives thereof,including analogues and homologues. In an embodiment of the inventionsaid one or more cannabinoids comprises cannabidiol (CBD). In anembodiment of the invention said one or more cannabinoids is CBD.

In an embodiment of the invention, the one or more cannabinoids comprisetetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),tetrahydrocannabivarin (THCV), salts and derivatives thereof. In anembodiment of the invention said one or more cannabinoids comprisestetrahydrocannabinol (THC). Preferably THC is intended to mean(-)-trans-Δ⁹-tetrahydrocannabinol, i.e.(6aR,10aR)-delta-9-tetrahydrocannabinol). In an embodiment of theinvention said one or more cannabinoids is THC.

In an embodiment of the invention, the one or more cannabinoids comprisecannabigerol (CBG), salts and derivatives thereof.

In an embodiment of the invention, the one or more cannabinoids compriseat least two cannabinoids. In an embodiment of the invention said one ormore cannabinoids comprises a combination of several cannabinoids, suchas THC and CBD. In an embodiment of the invention said one or morecannabinoids is a combination of THC and CBD.

In an embodiment of the invention the chewing gum comprises gum base inan amount of 30-75% by weight of the chewing gum before any optionallyapplied coating, such as 35-70% by weight of the chewing gum or 40-65%by weight of the chewing gum or 45-60% by weight of the chewing gum.

In an embodiment of the invention the chewing gum comprises wax. In anembodiment of the invention the chewing gum comprises fat.

In an embodiment of the invention the chewing gum comprises flavor in anamount between 0.01 and 10% by weight of the chewing gum such as in anamount between 0.01 and 5% by weight of the chewing gum.

According to an advantageous embodiment of the invention, the chewinggum may be formulated with flavors, e.g. flavors including acids, whichmay be more acceptable for seriously ill patients, such as patientsreceiving chemotherapy.

In an embodiment of the invention the chewing gum is manufactured in atwo-step process, the first step including the process of providing gumbase in a first mixing process and a further step including the processof mixing gum base with further chewing gum components in a furthermixing process. In an embodiment of the invention the chewing gum ismanufactured in a one step process by means of an extruder. This isreferred to as extruded chewing gum.

In an embodiment of the invention, the one or more cannabinoids arepresent in solid form. In an embodiment of the invention, the one ormore cannabinoids are present in liquid or semi-liquid form. In anembodiment of the invention, the one or more cannabinoids are present ingranules

In an embodiment of the invention, the one or more cannabinoids arepresent in a pre-mixture with one or more sugar alcohols or saccharose.

In the present context, a pre-mixture is mainly used to allocate the oneor more cannabinoids properly to the manufacturing process and securethat the uniformity is not compromised and that the cannabinoids aredistributed properly into the mixture. Preferably, the cannabinoids areprovided in a premixture with one or more sugar alcohols. It was asurprise to the inventors that a premixture was important to have thecannabinoids distributed properly in the manufacturing process and toend up with a product where the uniformity was consistent.

In an embodiment of the invention, the one or more cannabinoids formpart of a complex with cyclodextrin. This complex may enhance therelease of cannabinoids according to the present invention.

In an embodiment of the invention, the one or more cannabinoids compriseat least one phytocannabinoid that forms part of an extract. In someembodiments of the invention, it was seen that cannabinoids as part ofan extract may enhance the release of cannabinoids. It was also seenthat the lower concentration applied in the extract, the higher release.

In an embodiment of the invention, the chewing gum further comprisingterpenes, such as at least one terpene that forms part of an extract.

In an embodiment of the invention, the one or more cannabinoids compriseat least one isolated cannabinoid.

In an embodiment of the invention, the one or more cannabinoids compriseat least one water-soluble cannabinoid. Water-soluble cannabinoids mayenhance the release according to the present invention.

In an embodiment of the invention, the chewing gum comprises one or moreemulsifiers.

In an embodiment of the invention the chewing gum comprises emulsifiersin an amount of 0.1% to 25% by weight of said chewing gum, such as 1-10%by weight of said chewing gum, such as 2-8% by weight of said chewinggum.

In an embodiment of the invention the emulsifiers are selected from thegroup of acetylated monoglycerides, mono- and/or di-glycerides of fattyacids such as glycerol monostearate, acetem, lecithin and anycombination thereof.

In an embodiment of the invention, the chewing gum comprises one or moresolubilizers.

In an embodiment of the invention, the chewing gum comprises aself-emulsifying agent.

In an embodiment of the invention, the chewing gum comprises a polymercarrier for the one or more cannabinoids.

In an embodiment of the invention, the chewing gum comprises a lipidcarrier for the one or more cannabinoids.

In an embodiment of the invention, the chewing gum comprises enzymeinhibitors.

In an embodiment of the invention, the chewing gum comprises one or moreantioxidants.

In an embodiment of the invention, the one or more cannabinoids have asystemic effect.

In an embodiment of the invention, the one or more cannabinoids have alocal effect.

In an embodiment of the invention, the one or more cannabinoids arecomprised in an outer coating of the chewing gum.

In certain embodiments of the invention, the cannabinoids are present inthe coating of the chewing gum. This is particularly preferred when anenhanced release of cannabinoids are preferred. Also, if controlledrelease of cannabinoids is preferred, it is an advantage to allocatecannabinoids in the coating. It was not expected by the inventors of thepresent invention that it was possible to use a coating to delivercannabinoids. By combining cannabinoids in the coating and in thechewing gum, controlled release of cannabinoids may be provided. In thepresent context, cannabinoids may both be allocated in the coating, inthe chewing gum or in both places.

In another aspect of the invention, the chewing gum of the presentinvention may be used for the treatment or alleviation of a medicalcondition.

In certain embodiments of the invention, the chewing gum of the presentinvention may be used for the treatment or alleviation of pain,epilepsy, cancer, nausea, inflammation, congenital disorders,neurological disorders, oral infections, dental pain, sleep apnea,psychiatric disorders, gastrointestinal disorders, inflammatory boweldisease, appetite loss, diabetes and fibromyalgia.

In the present context, the chewing gum of the invention may be appliedfor the medical indications as single indications from the list ofindications. The invention may also be applied for other medicalindications and indications that are not medical for instance localconditions in the mouth, such as bacterial infections or gingivitis,that may be treated or alleviated with the formulation of the presentinvention. The list is not exhaustive and other indications are part ofthe present invention.

In another aspect of the invention, a package is provided comprising achewing gum according to the invention, the package comprising amaterial acting as a barrier for the one or more cannabinoids andoxygen, preferably a copolymer of acrylonitrile and methyl acrylate.

In certain embodiments of the invention, the package comprising achewing gum according to the invention, wherein the package includes aliquid or a semisolid for the provision of a preventive environmenttherein.

In certain embodiments of the invention, the package comprising achewing gum according to the invention, wherein the package is a blisterpackage.

In another aspect of the invention, there is provided a methodcomprising the steps of providing water-insoluble gum base,water-soluble chewing gum ingredients, one or more high intensitysweeteners and one or more cannabinoids, and mixing the ingredientsunder elevated temperature for a period of time, and subsequentlyextruding the final composition to obtain a chewing gum.

In certain embodiments of the method, the method comprises mixing afirst amount of the water-soluble chewing gum ingredients into thewater-insoluble gum base under elevated temperature to obtain a mixtureof gum base and water-soluble chewing gum ingredients, and mixing asecond amount of water-soluble chewing gum ingredients into the mixtureafter a period of time and mixing the one or more cannabinoids into themixture after a period of time.

In certain embodiments of the method, the first amount of water-solublechewing gum ingredients comprise one or more sugar alcohols.

In certain embodiments of the method, the second amount of water-solublechewing gum ingredients comprise one or more sugar alcohols.

In certain embodiments of the method, the one or more cannabinoids aremixed into the mixture at about the same time as mixing the secondamount of water-soluble chewing gum ingredients into the mixture.

In certain embodiments of the method, the one or more cannabinoids aremixed into the mixture after a period of time of more than half thetotal mixing time.

In certain embodiments of the method, the one or more cannabinoids aremixed into the mixture as close as possible to the end of mixing whileat the same time securing that the one or more cannabinoids arehomogeneously distributed in the water-insoluble gum base.

In certain embodiments of the method, the one or more cannabinoids areincluded in a pre-mixture prior to mixing, the pre-mixture comprisingone or more sugar alcohols.

In certain embodiments of the method, the method comprises a step ofadding an outer coating to the chewing gum.

In certain embodiments of the method, the one or more cannabinoids arecomprised in the outer coating of the chewing gum.

In certain embodiments of the method, the chewing gum is formulatedaccording to any of the product embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in more details with respect tocertain aspects and embodiments of the invention. These aspects andembodiments are intended to be understood in connection with the rest ofthe description, including the Summary of the Invention and Examples ofthe invention.

The verb “to comprise” as is used in this description and in the claimsand its conjugations are used in its non-limiting sense to mean thatitems following the word are included, but items not specificallymentioned are not excluded. In addition, reference to an element by theindefinite article “a” or “an” does not exclude the possibility thatmore than one of the elements are present, unless the context clearlyrequires that there is one and only one of the elements. The indefinitearticle “a” or “an” thus usually means “at least one”. Additionally, thewords “a” and “an” when used in the present document in concert with theword comprising or containing denote “one or more.”

By the terms “gum base” and “gum base matrix” is meant the mainlywater-insoluble ingredients and hydrophobic gum base ingredients thatare mixed together, typically before the bulk portion of the chewing gumis added. The “gum base” may contain gum base polymers and plasticizers,waxes, emulsifiers, fats and/or fillers. The gum base may thus designatethe typical water-insoluble chewing gum components, which may bemanufactured in a first step and subsequently mixed with the mainlywater soluble portion in a second step. The term gum base may,evidently, also refer to the relevant gum base components that may befed into an extruder and forming part of the final chewing gum whenmixed with the chewing gum components in the extruder.

The term “bulk portion” or “water-soluble ingredients” intends to meanthe mainly water-soluble and hydrophilic chewing gum ingredients thatmay be mixed into the gum base matrix, either in a separate process orin a one-step process by means of an extruder.

The term “weight of the chewing gum” or similar wording meaning the sameis defined in the present context as weight of the chewing gum, notincluding the weight of an outer coating, such as a hard coating, softcoating, and the like.

By the phrase “texture” is meant a qualitative measure of theviscoelastic properties of the chewing gum and of the overall mouth-feelexperienced by the user during the chewing process. Thus, the term“texture” encompasses measurable quantities such as hardness andelasticity as well as more subjective parameters related to thechew-feel experienced by a user.

The term “in vivo chewing” intends to mean that the chewing gum systemis chewed by a human subject in an experimental setup of trained testpersons according to statistically principles and that either the salivaof the human subject is subject to measurements or the chewed chewinggum is subject to measurements, the experimental setup being performedat a chewing frequency of 60 chews per minute.

The term “in vivo release” or “in vivo testing of release” or similarwording intends to mean that the chewing gum is tested according toExample 24.

The term “in vitro release” or “in vitro testing of release” or similarwording intends to mean that the chewing gum is tested according toExample 25, in particular according to Dissolution Test for ChewingGums, General Monograph 2.9.25. In European Pharmacopoeia, 5th ed.

The term “release” in the present context is intended to mean under “invivo” or “in vitro” conditions. In particular, the “release rate” duringa certain period of time is intended to mean the amount in percentage ofcannabinoids that is released during the period at a chewing frequencyof 60 chews per minute.

The term “sustained release” or “extended release” is herein intended tomean prolonged release over time. The term “rapid release” or “quickrelease” or “high release” is herein intended to mean a higher contentreleased for a given period of time. The term “controlled release” isintended to mean a release of a substance from a gum by the aid ofactive chewing of the gum in the oral cavity of the subject, whereby theactive chewing is controlling the amount of substance released.

The term “delivery to the oral mucosa” or similar wording intends tomean that the chewing gum is tested according to Example 27.

A “self-emulsifying agent” is an agent which will form an emulsion whenpresented with an alternate phase with a minimum energy requirement. Incontrast, an emulsifying agent, as opposed to a self-emulsifying agent,is one requiring additional energy to form an emulsion.

The term “natural resin”, as used herein, means resinous compounds beingeither polyterpene derived from terpenes of natural origin or resinouscompounds derived from gum rosin, wood rosin or tall-oil rosin.

The gum base is the masticatory substance of the chewing gum, whichimparts the chew characteristics to the final product. The gum basetypically defines the release profile and plays a significant role inthe gum product. The gum base portion is retained in the mouththroughout the chew. The water-soluble portion disappears over a periodof time during chewing.

According to embodiments of the invention, a preferred amount of gumbase matrix in the final chewing gum is 30 -75% by weight of the chewinggum before any optionally applied coating, such as 35-70% by weight ofthe chewing gum or 40-65% by weight of the chewing gum or 45-60% byweight of the chewing gum.

Elastomers provide the rubbery, elastomeric and bouncing nature to thegum, which varies depending on this ingredient's chemical structure andhow it may be compounded with other ingredients. Elastomers suitable foruse in the gum base and gum of the present invention may include naturalor synthetic types. Polyvinyl acetate elastomer plasticizers are notconsidered elastomers according to the invention.

Elastomers may be selected from the group consisting ofstyrene-butadiene copolymers, polyisobutylene, isobutylene-isoprenecopolymers, polyethylene, polyurethane or any combination thereof.Preferred elastomers are styrene-butadiene copolymers (SBR),polyisobutylene and isobutylene-isoprene copolymers (BR).

Butadiene-styrene type elastomers, or SBR as they may be called,typically are copolymers of from about 20:80 to 60:40 styrenes:butadienemonomers. The ratio of these monomers affects the elasticity of the SBRas evaluated by mooney viscosity. As the styrene:butadiene ratiodecreases, the mooney viscosity decreases.

The structure of SBR typically consists of straight chain 1,3-butadienecopolymerized with phenylethylene (styrene). The average molecularweight of SBR is <600.000 g/mole.

[own] Isobutylene-isoprene type elastomers, or butyl as they may becalled, have molar percent levels of isoprene ranging from 0.2 to 4.0.Similar to SBR, as the isoprene:isobutylene ratio decreases, so does theelasticity, measured by mooney viscosity.

The structure of butyl rubber typically consists of branched2-methyl-1,3-butadiene (isoprene) copolymerized with branched2-methylpropene (isobutylene). The average molecular weight of SBR is inthe range from 150.000 g/mole to 1.000.000 g/mole.

Polyisobutylene, or PIB as they may be called, type elastomers arepolymers of 2-methylpropeneThe low molecular weight elastomers providesoft chew characteristics to the gum base and still provide the elasticqualities as do the other elastomers. Average molecular weights mayrange from about 30,000 to 120,000 g/mole and the penetration may rangefrom about 4 millimeters to 20 millimeters. The higher the penetration,the softer the FIB. Similar to the SBR and butyl, the high molecularweight elastomers provide elasticity the gum. Average molecular weightmay range from 120.000 to 1.000.000 g/mole.

Polybutene range in average molecular weight from about 5.000 g/mole toabout 30.000 g/mole.

Useful natural elastomers include natural rubber such as smoked orliquid latex and guayule, natural gums such as jelutong, lechi caspi,perillo, sorva, massaranduba balata, massaranduba chocolate, nispero,rosidinha, chicle, gutta percha, gutta kataiu, niger gutta, tunu,chilte, chiquibul, gutta hang kang. Natural elastomers may also beapplied in aspects of the present invention.

Elastomer plasticizers vary the firmness of the gum base. Theirspecificity on elastomer inter-molecular chain breaking (plasticizing)along with their varying softening points cause varying degrees offinished gum firmness and compatibility when used in base. Polyvinylacetate elastomers plasticizers are examples of elastomer plasticizersof the present invention.

In some embodiments of the invention, the weight-average molecularweight (Mw) of the one or more polyvinyl acetate elastomer plasticizersis from 5,000 to 40,000. In some embodiments of the invention, theweight-average molecular weight (Mw) of the one or more polyvinylacetate elastomer plasticizers is from 6,000 to 35,000. In someembodiments of the invention, the weight-average molecular weight (Mw)of the one or more polyvinyl acetate elastomer plasticizers is from7,000 to 30,000. In some embodiments of the invention, theweight-average molecular weight (Mw) of the one or more polyvinylacetate elastomer plasticizers is from 8,000 to 25,000. In someembodiments of the invention, the weight-average molecular weight (Mw)of the one or more polyvinyl acetate elastomer plasticizers is from10,000 to 20,000.

In some embodiments of the invention, the viscosity of the one or morepolyvinyl acetate elastomer plasticizers is from 1.0 to 3.0 mPa*s asmeasured according to ASTM D445-06 (10 wt. % in ethyl acetate), such asfrom 1.0 to 2.5 mPa*s.

In some embodiments of the invention, the K value of the one or morepolyvinyl acetate elastomer plasticizers is from 15 to 33 as measuredaccording to DIN 53726 (1 wt. % in acetone), such as from 18 to 30.

Generally, the term “polyvinyl acetate elastomer plasticizer” isintended to mean polyvinyl acetate having a weight-average molecularweight (Mw) of less than about 40,000.

Generally, the term “polyvinyl acetate elastomer” is intended to meanpolyvinyl acetate having a weight-average molecular weight (Mw) of morethan about 40,000.

In certain embodiments of the invention, the gum base comprises lessthan 10% by weight of polyvinyl acetate elastomer. In certainembodiments of the invention, the gum base comprises less than 5% byweight of polyvinyl acetate elastomer. In certain embodiments of theinvention, the gum base comprises 2 to 6% by weight of polyvinyl acetateelastomer. In certain embodiments of the invention, the gum basecomprises 3 to 5% by weight of polyvinyl acetate elastomer. In certainembodiments of the invention, the gum base is substantially free ofpolyvinyl acetate elastomer

In certain embodiments of the invention, the gum base comprises 15-35%by weight of the one or more polyvinyl acetate elastomer plasticizersand less than 10% by weight of polyvinyl acetate elastomer. In certainembodiments of the invention, the gum base comprises 15-35% by weight ofthe one or more polyvinyl acetate elastomer plasticizers and less than5% by weight of polyvinyl acetate elastomer. In certain embodiments ofthe invention, the gum base comprises 15-35% by weight of the one ormore polyvinyl acetate elastomer plasticizers and 2 to 6% by weight ofpolyvinyl acetate elastomer.

Natural resins may be selected from ester gums including as examplesglycerol esters of partially hydrogenated rosins, glycerol esters ofpolymerized rosins, glycerol esters of partially dimerized rosins,glycerol esters of tally oil rosins, pentaerythritol esters of partiallyhydrogenated rosins, methyl esters of rosins, partially hydrogenatedmethyl esters of rosins, pentaerythritol esters of rosins, syntheticresins such as terpene resins derived from alpha-pinene, beta-pinene,and/or d-limonene, and natural terpene resins.

In an embodiment of the invention, the chewing gum comprises furtherchewing gum ingredients selected from the group consisting of flavors,dry-binders, tableting aids, anti-caking agents, emulsifiers,antioxidants, enhancers, absorption enhancers, high intensitysweeteners, softeners, colors, active ingredients, water-solubleindigestible polysaccharides, water-insoluble polysaccharides or anycombination thereof.

According to embodiments of the invention, the emulsifiers may beselected from the group consisting of sucrose ester of fatty acids (suchas sucrose mono stearate), polyethylene glycol esters or ethers (PEG)(such as caprylocaproyl macrogol-8 glycerides and lauroylmacrogol-32-glycerides), mono- and diglyceride of fatty acids (such asglycerol monostearate, glycerol monolaurate, glyceryl behenate ester),acetic acid esters of mono- and diglycerides of fatty acids (Acetem),polyoxyethylene alkyl ethers, diacetyl tartaric ester of monoglycerides,lactylated monoglycerides, glycerophospholipids (such as lecithin),poloxamer (non-ionic block copolymer of ethylene oxide and propyleneoxide), cyclodextrins, fatty acid esters of sorbitol (such as sorbitanmonolaurate, sorbitan monostearate, sorbitan tristearate, polysorbates).Self-emulsifying emulsifiers may be phospholipids (Lecithin),Polysorbates (polysorbate 80).

SEDDS (self-emulsifying drug delivery system) may consist of hard orsoft capsules filled with a liquid or a gel that consists ofself-emulsifiers, one or more cannabinoids, oil (to dissolve thecannabinoids) and a surfactant. SEDDS may comprise of a blend or mixtureof self-emulsifiers, one or more cannabinoids, oil (to dissolve thecannabinoids) and a surfactant. SEDDS may comprise granules comprisingself-emulsifiers, one or more cannabinoids, oil (to dissolve thecannabinoids) and a surfactant. Upon contact with gastric fluid, theSEDDS spontaneously emulsify due to the presence of surfactants. Manysurfactants, however, are lipid based and interact with lipases in theGIT (gastro intestinal tract). This can lead to a reduced capability ofthe lipid-based surfactants to emulsify the one or more cannabinoids aswell as the oil carrier, both reducing bioavailability.

According to embodiments of the invention, flavors may be selected fromthe group consisting of coconut, coffee, chocolate, vanilla, grapefruit, orange, lime, menthol, liquorice, caramel aroma, honey aroma,peanut, walnut, cashew, hazelnut, almonds, pineapple, strawberry,raspberry, tropical fruits, cherries, cinnamon, peppermint, wintergreen,spearmint, eucalyptus, and mint, fruit essence such as from apple, pear,peach, strawberry, apricot, raspberry, cherry, pineapple, and plumessence. The essential oils include peppermint, spearmint, menthol,eucalyptus, clove oil, bay oil, anise, thyme, cedar leaf oil, nutmeg,and oils of the fruits mentioned above.

Petroleum waxes aid in the curing of the finished gum made from the gumbase as well as improve shelf life and texture. Wax crystal sizeinfluences the release of flavor. Those waxes high in iso-alkanes have asmaller crystal size than those waxes high in normal-alkanes, especiallythose with normal-alkanes of carbon numbers less than 30. The smallercrystal size allows slower release of flavor since there is morehindrance of the flavors escape from this wax versus a wax having largercrystal sizes.

Petroleum wax (refined paraffin and microcrystalline wax) and paraffinwax are composed of mainly straight-chained normal-alkanes and branchediso-alkanes. The ratio of normal-alkanes to iso-alkanes varies.

Antioxidants prolong shelf life and storage of gum base, finished gum ortheir respective components including fats and flavor oils.

Antioxidants suitable for use in gum base include butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), betacarotenes,tocopherols, acidulants such as Vitamin C (ascorbic acid orcorresponding salts (ascorbates)), propyl gallate, catechins, othersynthetic and natural types or mixtures thereof.

Further chewing gum ingredients, which may be included in the chewinggum according to the present invention, include surfactants and/orsolubilizers. As examples of types of surfactants to be used assolubilizers in a chewing gum composition according to the invention,reference is made to H.P. Fiedler, Lexikon der Hilfstoffe fur Pharmacie,Kosmetik and Angrenzende Gebiete, pages 63-64 (1981) and the lists ofapproved food emulsifiers of the individual countries. Anionic,cationic, amphoteric or non-ionic solubilizers can be used. Suitablesolubilizers include lecithin, polyoxyethylene stearate, polyoxyethylenesorbitan fatty acid esters, fatty acid salts, mono and diacetyl tartaricacid esters of mono and diglycerides of edible fatty acids, citric acidesters of mono and diglycerides of edible fatty acids, saccharose estersof fatty acids, polyglycerol esters of fatty acids, polyglycerol estersof interesterified castor oil acid (E476), sodium stearoyllatylate,sodium lauryl sulfate and sorbitan esters of fatty acids andpolyoxyethylated hydrogenated castor oil (e.g. the product sold underthe trade name CREMOPHOR), block copolymers of ethylene oxide andpropylene oxide (e.g. products sold under trade names PLURONIC andPOLOXAMER), polyoxyethylene fatty alcohol ethers, polyoxyethylenesorbitan fatty acid esters, sorbitan esters of fatty acids andpolyoxyethylene steraric acid esters.

Particularly suitable solubilizers are polyoxyethylene stearates, suchas for instance polyoxyethylene(8)stearate andpolyoxyethylene(40)stearate, the polyoxyethylene sorbitan fatty acidesters sold under the trade name TWEEN, for instance TWEEN 20(monolaurate), TWEEN 80 (monooleate), TWEEN 40 (monopalmitate), TWEEN 60(monostearate) or TWEEN 65 (tristearate), mono and diacetyl tartaricacid esters of mono and diglycerides of edible fatty acids, citric acidesters of mono and diglycerides of edible fatty acids, sodiumstearoyllatylate, sodium laurylsulfate, polyoxyethylated hydrogenatedcastor oil, blockcopolymers of ethylene oxide and propyleneoxide andpolyoxyethylene fatty alcohol ether. The solubilizer may either be asingle compound or a combination of several compounds. In the presenceof an active ingredient, such as the included one or more cannabinoids,the chewing gum may preferably also comprise a carrier known in the artsof chewing gum and active ingredients. Poloxamer F68 is a further highlysuitable solubilizer.

High intensity artificial sweetening agents can also be used accordingto preferred embodiments of the invention. Preferred high intensitysweeteners include, but are not limited to sucralose, aspartame, saltsof acesulfame, alitame, neotame, saccharin and its salts, cyclamic acidand its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, monkfruit extract, advantame, stevioside and the like, alone or incombination.

In order to provide longer lasting sweetness and flavor perception, itmay be desirable to encapsulate or otherwise control the release of atleast a portion of the artificial sweeteners.

Techniques such as wet granulation, wax granulation, spray drying, spraychilling, fluid bed coating, conservation, encapsulation in yeast cellsand fiber extrusion may be used to achieve desired releasecharacteristics. Encapsulation of sweetening agents can also be providedusing another chewing gum component such as a resinous compound.

Usage level of the high-intensity sweetener will vary considerably andwill depend on factors such as potency of the sweetener, rate ofrelease, desired sweetness of the product, level and type of flavor usedand cost considerations. Thus, the active level of artificial sweetenermay vary from about 0.001 to about 8% by weight (preferably from about0.02 to about 8% by weight). When carriers used for encapsulation areincluded, the usage level of the encapsulated high-intensity sweetenerwill be proportionately higher.

A chewing gum and/or gum base may, if desired, include one or morefillers/texturizers including as examples, magnesium- and calciumcarbonate, sodium sulphate, ground limestone, silicate compounds such asmagnesium- and aluminum silicate, kaolin and clay, aluminum oxide,silicium oxide, talc, titanium oxide, mono-, di- and tri-calciumphosphates, cellulose polymers, such as wood, and combinations thereof.According to an embodiment of the invention, one preferredfiller/texturizer is calcium carbonate.

A number of chewing gum components well known within the art may beapplied within the scope of the present invention. Such componentscomprise but are not limited to waxes, fats, softeners, fillers, bulksweeteners, flavors, antioxidants, emulsifiers, coloring agents, bindingagents and acidulants.

In an embodiment of the invention, water-soluble ingredients comprise atleast one sugar alcohol. The at least one sugar alcohol may be selectedfrom the group consisting of xylitol, sorbitol, mannitol, maltitol,isomaltitol, isomalt, erythritol, lactitol, maltodextrin, hydrogenatedstarch hydrolysates, and combinations thereof.

A specific example of one category of polyol sweeteners include sugars,in particular a sugar selected from the group consisting of dextrose,sucrose, maltose, fructose, lactose, and combinations thereof.

A method of manufacturing extruded chewing gum may be as follows:

Gum bases are typically prepared by adding an amount of the elastomer,elastomer plasticizer and filler to a heated (100° C.-120° C.) sigmablade mixer with a front to rear speed ratio of from about 1.2:1 toabout 2:1, the higher ratio typically being used for gum base whichrequires more rigorous compounding of its elastomers.

The initial amounts of ingredients comprising the initial mass may bedetermined by the working capacity of the mixing kettle in order toattain a proper consistency and by the degree of compounding desired tobreak down the elastomer and increase chain branching. The higher thelevel of filler at the start or selection of a filler having a certainparticle size distribution, the higher the degree of compounding andthus more of the elastomeric chain crosslinking are broken, causing morebranching of the elastomer thus lower viscosity gum bases and thussofter final gum base and gum made from such a gum base. The longer thetime of compounding, the use of lower molecular weight or softeningpoint gum base ingredients, the lower the viscosity and firmness of thefinal gum base.

Compounding typically begins to be effective once the ingredients havemassed together. Anywhere from 15 minutes to 90 minutes may be thelength of compounding time.

Preferably, the time of compounding is from 20 minutes to about 60minutes. The amount of added elastomer plasticizer depends on the levelof elastomer and filler present. If too much elastomer plasticizer isadded, the initial mass becomes over plasticized and not homogeneous.

After the initial ingredients have massed homogeneously and compoundedfor the time desired, the balance of the gum base ingredients are addedin a sequential manner until a completely homogeneous molten mass isattained. Typically, any remainder of elastomer, elastomer plasticizerand filler, are added within 60 minutes after the initial compoundingtime. The filler and the elastomer plasticizer would typically beindividually weighed and added in portions during this time. Theoptional waxes, softeners and antioxidants are typically added after theelastomer and elastomer plasticizers and during the next 60 minutes.Then the mass is allowed to become homogeneous before dumping.

Typical gum base processing times may vary from about one to about threehours, preferably from about 1½ tp 2½ hours, depending on theformulation. The final mass temperature when dumped may be between 70°C. and 130° C. and preferably between 100° C. and 120° C. The completedmolten mass is emptied from the mixing kettle into coated or lined pans,extruded or cast into any desirable shape and allowed to cool andsolidify. Those skilled in the art will recognize that many variationsof the above described procedure may be followed.

The water-soluble portion of the chewing gum may comprise softeners,sweeteners, high intensity sweeteners, flavoring agents, acidulants,fillers, antioxidants, and other components that provide desiredattributes. Softeners typically constitute from about 0.5% to about25.0% by weight of the chewing gum. The bulking agents generallycomprise from about 5% to about 90%, preferably from about 20% to about80% of the chewing gum. High-intensity sweeteners in gum typically mayrange from about 0.01 to 0.50 weight percent. A flavoring agent may bepresent in the chewing gum in an amount within the range of from about0.1 to about 15.0 weight percent of the gum.

In general, chewing gum may be manufactured by sequentially adding thevarious chewing gum ingredients to a commercially available mixer knownin the art where the finished gum base is already present. After theinitial ingredients have been thoroughly mixed, the gum mass isdischarged from the mixer and shaped into the desired form such as byrolling into sheets and cutting into sticks, extruded into chunks orcasting into pellets.

Generally, the ingredients may be mixed by first melting the gum baseand adding it to the running mixer. Colors, active agents and/oremulsifiers may also be added at this time. A softener such as glycerinmay also be added at this time, along with syrup and a portion of thebulking agent/sweetener. Further portions of the bulking agent/sweetenermay then be added to the mixer. A flavoring agent is typically addedwith the final portion of the bulking agent/sweetener. A high-intensitysweetener is preferably added after the final portion of bulking agentand flavor have been added.

The entire mixing procedure typically takes from thirty to fortyminutes, but longer mixing times may sometimes be required. Thoseskilled in the art will recognize that many variations of the abovedescribed procedure may be followed.

In accordance with the invention, the chewing gum may comprise about 0.1to about 75% by weight of an outer coating applied onto the chewing gumcentre. Thus, suitable coating types include hard coatings, filmcoatings and soft coatings of any composition including those currentlyused in coating of chewing gum.

One presently preferred outer coating type is a hard coating, which termis used in the conventional meaning of that term including sugarcoatings and sugar-free (or sugarless) coatings and combinationsthereof. The object of hard coating is to obtain a sweet, crunchy layer,which is appreciated by the consumer and it may moreover protect the gumcentres for various reasons. In a typical process of providing thechewing gum centres with a protective sugar coating, the gum centres aresuccessively treated in suitable coating equipment with aqueoussolutions of crystallisable sugar such as sucrose or dextrose, which,depending on the stage of coating reached, may contain other functionalingredients, e.g. fillers, binding agents, colours, etc. In the presentcontext, the sugar coating may contain further functional or activecompounds including flavour compounds and/or active compounds.

In a typical hard coating process as it will be described in detail inthe following, a suspension containing crystallisable sugar and/orpolyol is applied onto the gum centres and the water it contains isevaporated off by blowing with air. This cycle must be repeated severaltimes, typically 3 to 80 times, in order to reach the swelling required.The term “swelling” refers to the increase in weight or thickness of theproducts, as considered at the end of the coating operation bycomparison with the beginning, and in relation to the final weight orthickness of the coated products. In accordance with the presentinvention, the coating layer constitutes about 0.1 to about 75% byweight of the finished chewing gum element, such as about 10 to about60% by weight, including about 15 to about 50% by weight.

In further useful embodiments, the outer coating of the chewing gumelement of the invention is an element that is subjected to a filmcoating process and which therefore comprises one or more film-formingpolymeric agents and optionally one or more auxiliary compounds, e.g.plasticizers, pigments and opacifiers. A film coating is a thinpolymer-based coating applied to a chewing gum centre of any of theabove forms. The thickness of such a coating is usually between 20 and100 μm. Generally, the film coating is obtained by passing the chewinggum centres through a spray zone with atomized droplets of the coatingmaterials in a suitable aqueous or organic solvent vehicle, after whichthe material adhering to the gum centres is dried before the nextportion of coating is received. This cycle is repeated until the coatingis complete.

In the present context, suitable film-coating polymers include ediblecellulose derivatives such as cellulose ethers including methylcellulose(MC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) andhydroxypropyl methylcellulose (HPMC). Other useful film-coating agentsare acrylic polymers and copolymers, e.g. methylacrylate aminoestercopolymer or mixtures of cellulose derivatives and acrylic polymers. Aparticular group of film-coating polymers, also referred to asfunctional polymers are polymers that, in addition to its film-formingcharacteristics, confer a modified release performance with respect toactive components of the chewing gum formulation. Such release modifyingpolymers include methylacrylate ester copolymers, ethylcellulose (EC)and enteric polymers designed to resist the acidic stomach environment.The latter group of polymers include: cellulose acetate phthalate (CAP),polyvinyl acetate phthalate (PVAP), shellac, methacrylic acidcopolymers, cellulose acetate trimellitate (CAT) and HPMC. It will beappreciated that the outer film coating according to the presentinvention may comprise any combination of the above film-coatingpolymers.

According to the invention, the one or more cannabinoids may be selectedfrom various cannabinoids.

“Cannabinoids” are a group of compounds including the endocannabinoids,the phytocannabinoids and those which are neither endocannabinoids orphytocannabinoids, hereinafter “syntho-cannabinoids”.

“Endocannabinoids” are endogenous cannabinoids, which are high affinityligands of CB1 and CB2 receptors.

“Phytocannabinoids” are cannabinoids that originate in nature and can befound in the cannabis plant. The phytocannabinoids can be present in anextract including a botanical drug substance, isolated, or reproducedsynthetically.

“Syntho-cannabinoids” are those compounds capable of interacting withthe cannabinoid receptors (CB1 and/or CB2) but are not foundendogenously or in the cannabis plant. Examples include WIN 55212 andrimonabant.

An “isolated phytocannabinoid” is one which has been extracted from thecannabis plant and purified to such an extent that the additionalcomponents such as secondary and minor cannabinoids and thenon-cannabinoid fraction have been removed.

A “synthetic cannabinoid” is one which has been produced by chemicalsynthesis. This term includes modifying an isolated phytocannabinoid,by, for example, forming a pharmaceutically acceptable salt thereof.

A “substantially pure” cannabinoid is defined as a cannabinoid which ispresent at greater than 95% (w/w) pure. More preferably greater than 96%(w/w) through 97% (w/w) thorough 98% (w/w) to 99% % (w/w) and greater.

A “highly purified” cannabinoid is defined as a cannabinoid that hasbeen extracted from the cannabis plant and purified to the extent thatother cannabinoids and non-cannabinoid components that are co-extractedwith the cannabinoids have been substantially removed, such that thehighly purified cannabinoid is greater than or equal to 95% (w/w) pure.

“Plant material” is defined as a plant or plant part (e.g. bark, wood,leaves, stems, roots, flowers, fruits, seeds, berries or parts thereof)as well as exudates, and includes material falling within the definitionof “botanical raw material” in the Guidance for Industry Botanical DrugProducts Draft Guidance, August 2000, US Department of Health and HumanServices, Food and Drug Administration Center for Drug Evaluation andResearch.

In the context of this application the terms “cannabinoid extract” or“extract of cannabinoids”, which are used interchangeably, encompass“Botanical Drug Substances” derived from cannabis plant material. ABotanical Drug Substance is defined in the Guidance for IndustryBotanical Drug Products Draft Guidance, August 2000, US Department ofHealth and Human Services, Food and Drug Administration Centre for DrugEvaluation and Research as: “A drug substance derived from one or moreplants, algae, or macroscopic fungi. It is prepared from botanical rawmaterials by one or more of the following processes: pulverisation,decoction, expression, aqueous extraction, ethanolic extraction, orother similar processes.” A botanical drug substance does not include ahighly purified or chemically modified substance derived from naturalsources. Thus, in the case of cannabis, “botanical drug substances”derived from cannabis plants do not include highly purified,Pharmacopoeial grade cannabinoids.

The term “Cannabis plant(s)” encompasses wild type Cannabis sativa andalso variants thereof, including cannabis chemovars which naturallycontain different amounts of the individual cannabinoids, Cannabissativa subspecies indica including the variants var. indica and var.kafiristanica, Cannabis indica, Cannabis ruderalis and also plants whichare the result of genetic crosses, self-crosses or hybrids thereof. Theterm “Cannabis plant material” is to be interpreted accordingly asencompassing plant material derived from one or more cannabis plants.For the avoidance of doubt it is hereby stated that “cannabis plantmaterial” includes dried cannabis biomass.

Preferably the one or more cannabinoids are selected from:cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD),cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG),cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol(CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO),tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA). More preferably the one or more cannabinoid is CBD or THC. This listis not exhaustive and merely details the cannabinoids which areidentified in the present application for reference.

So far, more than 120 different phytocannabinoids have been identifiedwhich are within the scope of the present invention.

Cannabinoids can be split into different groups as follows:Phytocannabinoids; Endocannabinoids; and Synthetic cannabinoids.

Cannabinoid receptors can be activated by three major groups of agonistligands, for the purposes of the present invention and whether or notexplicitly denominated as such herein, lipophilic in nature and classedrespectively as: endocannabinoids (produced endogenously by mammaliancells); phytocannabinoids (such as cannabidiol, produced by the cannabisplant); and, synthetic cannabinoids (such as HU-210).

Phytocannabinoids can be found as either the neutral carboxylic acidform or the decarboxylated form depending on the method used to extractthe cannabinoids. For example, it is known that heating the carboxylicacid form will cause most of the carboxylic acid form to decarboxylate.

Phytocannabinoids can also occur as either the pentyl (5 carbon atoms)or propyl (3 carbon atoms) variant. For example, the phytocannabinoidTHC is known to be a CB1 receptor agonist whereas the propyl variantTHCV has been discovered to be a CB1 receptor antagonist meaning that ithas almost opposite effects.

According to the invention, examples of phytocannabinoids may becannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD),cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG),cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol(CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO),tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA). More preferably the one or more cannabinoid is CBD or THC.

The formulation according to the present invention may also comprise atleast one cannabinoid selected from those disclosed in A. DouglasKinghorn et al., Phytocannabinoids, Vol. 103, Chapter 1, pages 1-30.

Examples of endocannabinoids are molecules that activate the cannabinoidreceptors within the body Examples include 2-arachidonyl glycerol (2AG),2-arachidonyl glyceryl ether (2AGE), arachidonyl dopamine, andarachidonyl ethanolamide (anandamide). Structurally related endogenousmolecules have been identified that share similar structural features,but that display weak or no activity towards the cannabinoid receptorsbut are also termed endocannabinoids. Examples of these endocannabinoidlipids include 2-acyl glycerols, alkyl or alkenyl glyceryl ethers, acyldopamines and N-acylethanolamides that contain alternative fatty acid oralcohol moieties, as well as other fatty acid amides containingdifferent head groups. These include N-acylserines as well as many otherN-acylated amino acids. Examples of cannabinoid receptor agonists areneuromodulatory and affect short-term memory, appetite, stress response,anxiety, immune function and analgesia.

Synthetic cannabinoids encompass a variety of distinct chemical classes:the cannabinoids structurally related to THC, the cannabinoids notrelated to THC, such as (cannabimimetics) including theaminoalkylindoles, 1,5-diarylpyrazoles, quinolines, andarylsulfonamides, and eicosanoids related to the endocannabinoids. Allor any of these cannabinoids can be used in the present invention.

It is preferred that the formulation comprises one or two primarycannabinoids, which are preferably selected from the group consistingof, cannabidiol (CBD) or cannabidivarin (CBDV), tetrahydrocannabinol(THC), tetrahydrocannabivarin (THCV), tetrahydrocannabinolic acid(THCA), cannabigerol (CBG) and cannabidiolic acid (CBDA) or acombination thereof. It is preferred that the formulation comprisescannabidiol and/or tetrahydrocannabinol.

Preferably, the chewing gum of the present invention may be used for thetreatment or alleviation of pain, epilepsy, cancer, nausea,inflammation, congenital disorders, neurological disorders, oralinfections, dental pain, sleep apnea, psychiatric disorders,gastrointestinal disorders, inflammatory bowel disease, appetite loss,diabetes and fibromyalgia.

In a further aspect of the present invention the oral cannabinoidformulation is suitable for use in the treatment of conditions requiringthe administration of a neuroprotectant or anti-convulsive medication.

The oral cannabinoid formulation may be for use in the treatment ofseizures.

The oral cannabinoid formulation may be for use in the treatment ofDravet syndrome, Lennox Gastaut syndrome, myoclonic seizures, juvenilemyoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms,West syndrome, infantile spasms, refractory infantile spasms, tuberoussclerosis complex, brain tumours, neuropathic pain, cannabis usedisorder, post-traumatic stress disorder, anxiety, early psychosis,Alzheimer's disease, and autism.

The following non-limiting examples illustrate different variations ofthe present invention. The examples are meant for indicating theinventive concept; hence the mentioned examples should not be understoodas exhaustive for the present. In particular, CBD is used as anexemplary compound, but may also be another cannabinoid.

EXAMPLES Example 1 Preparation of Gum Base

Twenty different water-insoluble gum bases were prepared. The gum baseswere prepared in the process as described below. In the subsequentexamples, the specific compositions of the gum bases (GB10 to GB29) areoutlined.

Elastomers and elastomer plasticizer (PVA) were mixed at 120° C.together with filler, either calcium carbonate or talc, in a mixerhaving horizontally placed Z-shaped arms for mixing. It is noted thatPVA was applied as an elastomer plasticizer for the elastomers in thecomposition and not in form of an elastomer. PVA as an elastomerplasticizer has special properties in the present context. For some ofthe comparative examples, another comparative polymer was added togetherwith the elastomers and elastomer plasticizer and mixed together withthe elastomer and the elastomer plasticizer.

Natural resins were added after about 30 minutes of mixing of thepolymers. After the polymers and the natural resin had softened in thecomposition, additional ingredients were added, such as triacetin,emulsifier, wax, antioxidants and vegetable fat.

After a total mixing time of about 45-60 minutes, the mixture wasdischarged into a pan and allowed to cool at room temperature.

For some of the examples where butyl rubber (BR) was added as anelastomer, the mixing time was optionally extended to a total of about90-105 minutes depending on the amount of optional fillers.

In all of the gum base examples, the amount of the various ingredientsis given as % by weight of the gum base.

Example 2 Various Gum Base Formulations

TABLE 1A GB number GB10 GB11 GB12 GB13 GB14 PVA 25 18 30 10 40 PIB 5 105 10 5 BR 5 5 5 5 — Nat. resin 25 20 20 35 15 Calcium Carbonate 17 — 1717 17 Talc — 17 — — — Triacetin — 7 — — — Emulsifier 5 10 5 5 5 Wax 1313 13 13 13 Veg. fat 5 — 5 5 5 Total 100 100 100 100 100 Gum basecompositions, PVA = polyvinyl acetate (Vinnapas B 1.5 sp., supplied byWacker); PIB = polyisobutylene (Oppanol B12, supplied by BASF); BR =butyl rubber (isobutylene-isoprene copolymer); Nat. resin = glycerolester of hydrogenated gum rosin; Veg. fat = vegetable fat.

Example 3 Various Gum Base Formulations

TABLE 1B GB number GB15 GB16 GB17 GB18 GB19 PVA 25 25 20 40 15 PIB 5 105 5 5 BR 5 5 5 5 — Nat. resin 25 20 30 10 40 Calcium Carbonate 17 17 1717 17 Talc — — — — — Triacetin — — — — — Emulsifier 5 5 5 5 5 Wax 13 1313 13 13 Veg. fat 5 5 5 5 5 Total 100 100 100 100 100 Gum basecompositions, PVA = polyvinyl acetate (Vinnapas B 1.5 sp., supplied byWacker); PIB = polyisobutylene (Oppanol B12, supplied by BASF); BR =butyl rubber (isobutylene-isoprene copolymer); Nat. resin = glycerolester of hydrogenated gum rosin; Veg. fat = vegetable fat.

Example 4 Various Gum Base Formulations

TABLE 1C GB number GB20 GB21 GB22 GB23 GB24 PVA 18 18 18 18 18 PIB 10 1010 10 10 BR 5 5 5 5 5 Nat. resin 20 20 20 20 20 Calcium Carbonate — — —— — Talc 14 16.5 13.5 17 14 Triacetin 7 7 7 7 7 Emulsifier 10 10 10 1010 Wax 13 13 13 13 13 Veg. fat — — — — — Acesulfame — 0.5 0.5 — —Menthol 3 — 3 — 3 BHT — — — 0.04 0.04 Total 100 100 100 100 100 Gum basecompositions, PVA = polyvinyl acetate (Vinnapas B 1.5 sp., supplied byWacker); PIB = polyisobutylene (Oppanol B12, supplied by BASF); BR =butyl rubber (isobutylene-isoprene copolymer); Nat. resin = glycerolester of hydrogenated gum rosin; Veg. fat = vegetable fat; Acesulfame K(HIS = high-intensity sweetener); Menthol (flavor); BHT (Butylatedhydroxytoluene = antioxidant).

Example 5 Various Gum Base Formulations

TABLE 1D GB number GB25 GB26 GB27 GB28 GB29 PVA 25 18 30 30 20 PIB 5 105 3 3 BR 5 5 — 2 2 Nat. resin 25 20 — — 20 VA-VL — — 20 20 10 CalciumCarbonate 17 — 17 17 17 Talc — 17 — — — Triacetin — 7 — — 2 Emulsifier 510 11 11 9 Wax 13 13 12 12 12 Veg. fat 5 — 5 5 5 Total 100 100 100 100100 Gum base compositions, PVA = polyvinyl acetate (Vinnapas B 1.5 sp.,supplied by Wacker); PIB = polyisobutylene (Oppanol B12, supplied byBASF); BR = butyl rubber (isobutylene-isoprene copolymer); Nat. resin =glycerol ester of hydrogenated gum rosin; VA-VL = vinyl acetate-vinyllaurate copolymer (Vinnapas B 500/40VL, supplied by Wacker); Veg. fat =vegetable fat.

Example 6 CBD Extract 52%

CBD extract with a 52% content of CBD provided by CBDepot (batch numberCSFF 2018/5) was preheated to around 60° C. for around 0.5 to 1 houruntil the extract was in liquid form. The extract had a content of fattyacids, glycerol, waxes, terpenes and flavonoids. After the preheatingprocess, the extract was either used directly together with additionalchewing gum ingredients, or the extract was applied in a premix.

Example 7 CBD Extract 10%

CBD extract with a 10% content of CBD provided by Medical Hemp (batchnumber MH131 B Gold), was preheated to around 60° C. for around 0.5 to 1hour until the extract was in liquid form. The extract had a content offatty acids, glycerol, waxes, terpenes and flavonoids. After thepreheating process, the extract was either used directly together withadditional chewing gum ingredients, or the extract was applied in apremix.

Example 8 CBD Isolate

CBD isolate from cannabis plant tissues (phytocannabinoid) with a 98.5%content of CBD provided by Medical Hemp (batch number MH18212) wasdissolved in an 96% ethanol solution. The ratio between the CBD isolateand ethanol was 1:1. Once CBD was dissolved in the ethanol, the CBDisolate was either used directly together with additional chewing gumingredients, or the extract was applied in a premix.

Example 9 Preparation of Cannabinoid Sugar Alcohol Premix

A premix was made with CBD and sugar alcohol particles, here sorbitol.The premix was made in a weight ratio of 1:5 of CBD and sorbitol witheither one of the forms of CBD outlined in Examples 6-8. CBD was addedto the sugar alcohol particles and homogenized gently.

Example 10 Preparation of Cannabinoid Cyclodextrin Premix

CBD (extract or isolate) was added and dissolved in a 5% solution ofpolysorbate 80 to obtain a 10% solution of CBD. The 10% CBD solution isslowly added and mixed into a solution with 10% cyclodextrin to form aCBD-cyclodextrin complex. The water is removed, whereupon the complexwas either used directly together with additional chewing gumingredients, or the complex was applied in a premix.

Example 11 Preparation of Cannabinoid Microcrystalline Cellulose Premix

A cannabinoid-microcrystalline cellulose (MCC) premix was made by firstadding free cannabinoid to poloxamer F68 (PF) to obtain a 10% blend ofcannabinoid in poloxamer F68. Butylated hydroxytoluene (BHT) was added(0.5%) to 50 grams of the cannabinoid-poloxamer F68 solid mix and addedto 50 grams of microcrystalline cellulose provided as Avicel PH 102 fromFMC Biopolymer. This was then mixed in a Kitchenaid mixer operated atabout 30 RPM for about 30 minutes at room temperature. This mixture wasequilibrated for about 30 minutes in a sealed container. Hereby, at 5%cannabinoid-MCC premix was obtained.

Example 12 Preparation of Cannabinoid Chewing Gum Formulation

Gum base (GB) prepared according to Example 1 and formulated accordingto Examples 2-5 was mixed with filler, here either talc, calciumcarbonate or sugar alcohol, in a 60 g mixer having horizontally placedZ-shaped arms for mixing. The mixer was preheated to a temperature ofapproximately 50° C. Once the content of the mixer was homogeneous,chewing gum ingredients were added according to a specified timeschedule.

Example 13 Preparation of Cannabinoid Chewing Gum Formulation withSpecific Order

Gum base (GB) prepared according to Example 1 and formulated accordingto Examples 2-5 was mixed with a filler, here sugar alcohol, in a 60 gmixer having horizontally placed Z-shaped arms for mixing. The mixer waspreheated to a temperature of approximately 50° C. Once the content ofthe mixer was homogeneous, chewing gum ingredients, includingwater-soluble ingredient, and cannabinoids were added according to aspecified time schedule as follows:

TABLE 1E It was secured that CBD was thoroughly mixed into thecomposition and that a homogeneous mixture was obtained. Sugar alcohol*was prepared as a premix with CBD according to Example 9. Here, thecontent in weight % is calculated as the sugar alcohol content,excluding the CBD content in the premix. CBD 52%* was prepared accordingto Example 6. Specified order of addition in the preparation of chewinggum Content in Application Ingredient weight % time in min. Gum base(GB) 40 0 Sugar alcohol 22.8 0 Maltitol syrup 8 3 Menthol powder 3 5Eucalyptus Powder 2 5 Acesulfame k 0.1 5 Sucralose 0.1 5 Sugar alcohol*5 8 CBD 52%* 1 8 Sugar alcohol 18 8 Total 100 13

Example 14 Composition of Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 13 was madewith the formulations outlined in the examples below. The formulationswere formed into chewing gum pieces by extrusion (rolling and scoring).The extruded chewing gum pieces had a weight of 1 g for each piece and acontent of CBD of 5 mg for each piece. In all of the chewing gumexamples, the amount of the various ingredients is given as % by weightof the chewing gum.

TABLE 1F It was secured that CBD was thoroughly mixed into thecomposition and that a homogeneous mixture was obtained. CBD 52%* wasprepared according to Example 6. CG Number CG100 CG101 CG102 CG103 CG104GB10 40 — — — — GB11 — 40 — — — GB12 — — 40 — — GB13 — — — 40 — GB14 — —— — 40 Sorbitol 45.8 45.8 45.8 45.8 45.8 Maltitol syrup 8 8 8 8 8Menthol powder 3 3 3 3 3 Eucalyptus Powder 2 2 2 2 2 Acesulfame k 0.10.1 0.1 0.1 0.1 Sucralose 0.1 0.1 0.1 0.1 0.1 CBD 52%* 1 1 1 1 1 Total100 100 100 100 100

Example 15 Composition of Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 13 was madewith the formulations outlined in the examples below. The formulationswere formed into chewing gum pieces by extrusion (rolling and scoring).The extruded chewing gum pieces had a weight of 1 g for each piece and acontent of CBD of 5 mg for each piece. In all of the chewing gumexamples, the amount of the various ingredients is given as % by weightof the chewing gum.

TABLE 1G It was secured that CBD was thoroughly mixed into thecomposition and that a homogeneous mixture was obtained. CBD 52%* wasprepared according to Example 6. CG Number CG105 CG106 CG107 CG108 CG109GB15 40 — — — — GB16 — 40 — — — GB17 — — 40 — — GB18 — — — 40 — GB19 — —— — 40 Sorbitol 45.8 45.8 45.8 45.8 45.8 Maltitol syrup 8 8 8 8 8Menthol powder 3 3 3 3 3 Eucalyptus Powder 2 2 2 2 2 Acesulfame k 0.10.1 0.1 0.1 0.1 Sucralose 0.1 0.1 0.1 0.1 0.1 CBD 52%* 1 1 1 1 1 Total100 100 100 100 100

Example 16 Composition of Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 13 was madewith the formulations outlined in the examples below. The formulationswere formed into chewing gum pieces by extrusion (rolling and scoring).The extruded chewing gum pieces had a weight of 1 g for each piece and acontent of CBD of 5 mg for each piece. In all of the chewing gumexamples, the amount of the various ingredients is given as % by weightof the chewing gum.

TABLE 1H It was secured that CBD was thoroughly mixed into thecomposition and that a homogeneous mixture was obtained. CBD 52%* wasprepared according to Example 6. CG Number CG110 CG111 CG112 CG113 CG114GB20 40 — — — — GB21 — 40 — — — GB22 — — 40 — — GB23 — — — 40 — GB24 — —— — 40 Sorbitol 45.8 45.8 45.8 45.8 45.8 Maltitol syrup 8 8 8 8 8Menthol powder 3 3 3 3 3 Eucalyptus Powder 2 2 2 2 2 Acesulfame k 0.10.1 0.1 0.1 0.1 Sucralose 0.1 0.1 0.1 0.1 0.1 CBD 52%* 1 1 1 1 1 Total100 100 100 100 100

Example 17 Composition of Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 13 was madewith the formulations outlined in the examples below. The formulationswere formed into chewing gum pieces by extrusion (rolling and scoring).The extruded chewing gum pieces had a weight of 1 g for each piece and acontent of CBD of 5 mg for each piece. In all of the chewing gumexamples, the amount of the various ingredients is given as % by weightof the chewing gum.

TABLE 1I It was secured that CBD was thoroughly mixed into thecomposition and that a homogeneous mixture was obtained. CBD 52%* wasprepared according to Example 6. CG Number CG115 CG116 CG117 CG118 CG119GB25 40 — — — — GB26 — 40 — — — GB27 — — 40 — — GB28 — — — 40 — GB29 — —— — 40 Sorbitol 45.8 45.8 45.8 45.8 45.8 Maltitol syrup 8 8 8 8 8Menthol powder 3 3 3 3 3 Eucalyptus 2 2 2 2 2 Powder Acesulfame k 0.10.1 0.1 0.1 0.1 Sucralose 0.1 0.1 0.1 0.1 0.1 CBD 52%* 1 1 1 1 1 Total100 100 100 100 100

Example 18 Composition of Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 13 was madewith the formulations outlined in the examples below. The formulationswere formed into chewing gum pieces by extrusion (rolling and scoring).The extruded chewing gum pieces had a weight of 1 g for each piece and acontent of CBD of 5 mg for each piece. In all of the chewing gumexamples, the amount of the various ingredients is given as % by weightof the chewing gum.

TABLE 1J It was secured that CBD was thoroughly mixed into thecomposition and that a homogeneous mixture was obtained. CBD 52%* wasprepared according to Example 6. CG Number CG120 CG121 CG122 CG123 CG124GB10 40 40 GB11 — — 40 40 40 Sorbitol 30 45.8 30 35.8 45.8 Talc 15.8 —15.8 10 — Maltitol syrup 8 8 8 8 8 Menthol powder 3 3 3 3 3 Eucalyptus 22 2 2 2 Powder Acesulfame k 0.1 0.1 0.1 0.1 0.1 Sucralose 0.1 0.1 0.10.1 0.1 CBD 52%* 1 1 1 1 1 Total 100 100 100 100 100

Example 19 Composition of Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 13 was madewith the formulations outlined in the examples below. The formulationswere formed into chewing gum pieces by extrusion (rolling and scoring).The extruded chewing gum pieces had a weight of 1 g for each piece and acontent of CBD of 5 mg for each piece. In all of the chewing gumexamples, the amount of the various ingredients is given as % by weightof the chewing gum.

TABLE 1K It was secured that CBD was thoroughly mixed into thecomposition and that a homogeneous mixture was obtained. CBD 52%* wasprepared according to Example 6. CG Number CG125 CG126 CG127 CG128 CG129GB11 55.8 45.8 35.8 25.8 15.8 Sorbitol 30 40 50 60 70 Maltitol syrup 8 88 8 8 Menthol powder 3 3 3 3 3 Eucalyptus 2 2 2 2 2 Powder Acesulfame k0.1 0.1 0.1 0.1 0.1 Sucralose 0.1 0.1 0.1 0.1 0.1 CBD 52%* 1 1 1 1 1Total 100 100 100 100 100

Example 20 Composition of Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 13 was madewith the formulations outlined in the examples below. The formulationswere formed into chewing gum pieces by extrusion (rolling and scoring).The extruded chewing gum pieces had a weight of 1 g for each piece and acontent of CBD of 5 mg for each piece. In all of the chewing gumexamples, the amount of the various ingredients is given as % by weightof the chewing gum.

TABLE 1L It was secured that CBD was thoroughly mixed into thecomposition and that a homogeneous mixture was obtained. CBD isolate*was prepared according to Example 8. CBD 10%* was prepared according toExample 7. CBD 52%* was prepared according to Example 6. CG Number CG130CG131 CG132 CG133 CG134 GB10 40 40 — — — GB11 — — 40 40 40 Sorbitol 41.845.8 46.3 41.8 45.8 Maltitol syrup 8 8 8 8 8 Menthol powder 3 3 3 3 3Eucalyptus 2 2 2 2 2 Powder Acesulfame k 0.1 0.1 0.1 0.1 0.1 Sucralose0.1 0.1 0.1 0.1 0.1 CBD isolate* — — 0.5 — — CBD 10%* 5 — — 5 — CBD 52%*— 1 — — 1 Total 100 100 100 100 100

Example 21 Composition of Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 13 was madewith the formulations outlined in the examples below. The formulationswere formed into chewing gum pieces by extrusion (rolling and scoring).The extruded chewing gum pieces had a weight of 1 g for each piece and acontent of CBD of 5 mg for each piece. In all of the chewing gumexamples, the amount of the various ingredients is given as % by weightof the chewing gum.

TABLE 1M It was secured that CBD was thoroughly mixed into thecomposition and that a homogeneous mixture was obtained. CBD 52%* wasprepared according to Example 6. CG Number CG135 CG136 CG137 CG138 CG139GB11 40 40 40 40 40 Sorbitol 45.8 45.6 45.4 45.2 45.0 Maltitol syrup 8 88 8 8 Menthol powder 3 3 3 3 3 Eucalyptus 2 2 2 2 2 Powder Acesulfame k0.1 0.2 0.3 0.4 0.5 Sucralose 0.1 0.2 0.3 0.4 0.5 CBD 52%* 1 1 1 1 1Total 100 100 100 100 100

Example 22 Composition of Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 13 was madewith the formulations outlined in the examples below. The formulationswere formed into chewing gum pieces by extrusion (rolling and scoring).The extruded chewing gum pieces had a weight of 1 g for each piece and acontent of CBD of 5 mg for each piece. In all of the chewing gumexamples, the amount of the various ingredients is given as % by weightof the chewing gum.

TABLE 1N It was secured that CBD was thoroughly mixed into thecomposition and that a homogeneous mixture was obtained. CBD 52%* wasprepared according to Example 6. CBD-MCC 5%* was prepared according toExample 11. CBD-MCC 10%* was prepared according to Example 11 with ahigher amount of CBD. CBD-cyclodex* is CBD- cyclodextrin complexprepared according to Example 10. Self-emulsifying* was prepared with anemulsifier, here polysorbate. CG Number CG140 CG141 CG142 CG143 CG144GB11 40 40 40 40 40 Sorbitol 45.8 36.8 41.8 26.8 44.8 Maltitol syrup 8 88 8 8 Menthol powder 3 3 3 3 3 Eucalyptus 2 2 2 2 2 Powder Acesulfame k0.1 0.1 0.1 0.1 0.1 Sucralose 0.1 0.1 0.1 0.1 0.1 CBD 52%* 1 — — — 1CBD-MCC 5%* — 10 — — CBD-MCC 10%* — — 5 — — CBD-cyclodex* — — — 20 —Self-emulsifying*   — — — 1 Total 100 100 100 100 100

Example 23 Coating of Chewing Gum

A hard coating was prepared for selected samples with the followingcomposition:

TABLE 1O It was secured that CBD was thoroughly mixed into thecomposition and that a homogeneous mixture was obtained. CBD 52%* wasprepared according to Example 6. CBD isolate* was prepared according toExample 8. The coating was provided to samples of CG100 from Example 15.Hard coating Ingredients % by weight Number CG145 CG146 Maltitol 57 57Water 25.4 25.9 Mannitol 11 11 gummi arabicum 4 4 titandioxid 1 1Polysorbate 0.1 0.1 CBD 52%* 1.5 — CBD isolate* — 0.7 Total 100 100

The coating was applied as a pre-heated suspension as outlined above to1 g extruded chewing gum with the formulation of CG100 in Example 15,except that CBD 52% or CBD isolate was substituted with sorbitol inCG100. Hence, CBD was not present in the extruded gum, but only in thecoating. A total of 5 mg CBD was present in the coated tablet. Thesuspension was applied in 3 subsequent steps according to conventionalcoating techniques to a total of 0.45 g coating to the 1 g extruded gum.This corresponds to a ratio of extruded gum to coating on 70:30.

Example 24 In Vivo Testing of Release

A sample was chewed with a chewing frequency of 60 chews pr. minute for3 or 5 minutes in a test panel of 8 test persons. The test person was ahealthy person appointed on an objective basis according to specifiedrequirements. After 3 or 5 minutes, the content of CBD was measured inthe remaining chewing gum residue. The chewing gum was subject to triplemeasurements for each of the 8 test persons, giving a total of 24measurements for each sample. An average of the 24 measurements wascalculated and the weight % release was calculated based on the originalcontent of CBD in the sample. The content of CBD was measured in theremaining chewing gum residue. The chewing gum residue was positioned ina flask and weighted. Subsequently, an organic solvent was added fordissolution purposes, and the mixture was mixed on a laboratory shakerovernight. The organic phase was diluted and centrifuged. Thesupernatant was injected directly to an HPLC system and analyzed by anassay method.

Example 25 In Vitro Testing of Release

In vitro release of CBD was established by means of a chewing machine(Dissolution Test for Chewing Gums, General Monograph 2.9.25. InEuropean Pharmacopoeia, 5th ed). A chewing chamber was filled with 20 mlbuffer (phosphate buffer pH 7.4). The chewing gum sample was placed inthe chamber and the chewing machine was initiated at 20 degree Celsiuswith 1 chew per second. After 3 or 5 minutes of chewing, the machine wasstopped and the chewing gum sample (residue) was placed in a vial. Ifmore release time points are needed (release profile), the chewingbuffer must be exchanged with 20 ml of fresh buffer every five minutes.The content of CBD was measured in the remaining chewing gum residue.The chewing gum residue was positioned in a flask and weighted.Subsequently, an organic solvent was added for dissolution purposes, andthe mixture was mixed on a laboratory shaker overnight. The organicphase was diluted and centrifuged. The supernatant was injected directlyinto an HPLC system and analyzed by an assay method.

Example 26 Stability Testing Method

For stability testing, the ICH guideline is used; 25° C/60%RH (2 years),30° C/65%RH (1 year), 40° C/75%RH (3 month). All samples were packed induma bottles before stored in the conditions. All samples weresensorially and analytically evaluated. The content of CBD was measuredin the remaining chewing gum residue. The chewing gum residue waspositioned in a flask and weighted. Subsequently, an organic solvent wasadded for dissolution purposes, and the mixture was mixed on alaboratory shaker overnight. The organic phase was diluted andcentrifuged. The supernatant was injected directly into an HPLC set-upand analyzed by an assay method. The following method was able toseparate and quantify CBD, delta-9 THC, delta-8 THC and CBN.

Example 27 CBD Delivered to the Oral Mucosa

A sample was chewed in vivo with a chewing frequency of 60 chews pr.minute for 5 minutes in a test panel of 8 test persons. The test personwas not allowed to swallow during the procedure. After one minute,saliva was obtained from the test person and collected in a vessel forlater analysis. In tests for 5 minutes release, the same procedure wasfollowed until 5 minutes where the last sample was collected and addedto the same vessel for aggregated analysis. The test person was ahealthy person appointed on an objective basis according to specifiedrequirements. the aggregated saliva sample was collected after 5minutes, the content of CBD was measured in the saliva. The content ofCBD was also measured in the remaining chewing gum residue. The chewinggum residue was positioned in a flask and weighted. Subsequently, anorganic solvent was added for dissolution purposes, and the mixture wasmixed on a laboratory shaker overnight. The organic phase was dilutedand centrifuged. The supernatant was injected directly into an HPLCsystem and analyzed by an assay method. The gum and saliva was subjectto 3 triple measurements for each of the 8 test persons, giving a totalof 24 measurement for each sample. An average of the 24 measurements wascalculated and the weight % release was calculated. By comparing theamount of CBD in the remaining chewing gum residue and the amount of CBDin the saliva, the amount of CBD delivered to the oral mucosa could beestimated.

Example 28 Sensory Evaluation Test Set-Up

Apart from release measurements, either in vivo or in vitro, as well asstability tests of the extruded chewing gum, sensory tests were alsoperformed to reveal very important characteristics and properties of theextruded chewing gum. These sensory parameters are important asindicators of the structure of the chewing gum composition and thebehavior of the gum when chewed. The structure is the underlyingguidance as to how the chewing gum resembles the structure of acomparative chewing gum, which is set as the standard in the testseries, i.e. the chewing gums are compared to each other in the testseries. The test set-up was composed of 8 test persons in a test panel.Each of the test persons were healthy individuals appointed on anobjective basis according to specified requirements. The sensoryanalysis was performed according to ISO 4121-2003 in testing conditionsfollowing ISO 8589. The result is an average of the results of the 8individuals.

The test persons gave a rating from “+” to “+++++”, where “+” is poorand “+++++” is excellent and comparable to the standard, i.e. “+++++”means that the gum was comparable to the standard and “+” means that thegum was very far from comparable to the standard. “0” indicated that itwas not tested.

Five different parameters were tested in a test panel:

Initial chew Texture Flavor Sweetness Off-notes

“Initial chew”—the first impression of the gum when chewed within thefirst 30 seconds. For instance, a very hard and viscous structure gave avery low rating and a very brittle structure also gave a very lowrating.

“Texture”—the overall impression of the gum after 30 seconds of chewinggum or when the gum has gained the structure of a steady state. Forinstance, a very hard structure gave a very low rating and a very smoothstructure also gave a very low rating.

“Flavor”—the overall impression of the gum during chewing with respectto flavor. For instance, a very low flavor experience gave a very lowrating and a too high flavor experience that was not comparable to thestandard also gave a very low rating.

“Sweetness”—the overall impression of the taste of the gum duringchewing with respect to sweetness. For instance, if the sweetness wasdecreasing rapidly a very low rating was given and if the sweetness wastoo high giving an uncomfortable feeling a very low rating was alsogiven.

“Off-notes”—the overall impression of the off-note from the one or morecannabinoids in the composition during chewing. For instance, ifoff-notes (grass, bitter notes, irritation in the throat) wereexperienced in the throat, a low rating was given and if otheruncomfortable sensations was experienced a low rating was also given.

Example 29 ensory Evaluation of Cannabinoid Chewing Gum

Evaluation of Examples 14-22 according to Example 28 CG Initial chewTexture Flavor Sweetness Off-notes CG 100 +++++ +++++ ++++ ++++ ++++ CG101 +++++ +++++ ++++ ++++ ++++ CG 102 +++++ +++++ ++++ ++++ ++++ CG 103++++ +++ +++ ++++ ++++ CG 104 ++++ ++++ ++++ +++ ++++ CG 105 +++++ +++++++++ ++++ ++++ CG 106 +++++ +++++ ++++ ++++ ++++ CG 107 +++++ +++++ ++++++++ ++++ CG 108 ++++ +++ +++ +++ +++ CG 109 +++ ++++ ++++ +++ +++ CG110 0 0 +++++ ++++ +++++ CG 111 0 0 ++++ +++++ +++++ CG 112 0 0 ++++++++++ +++++ CG 113 0 0 ++++ ++++ ++++ CG 114 0 0 +++++ ++++ +++++ CG 115+++++ +++++ ++++ ++++ ++++ CG 116 +++++ +++++ ++++ ++++ ++++ CG 117 ++ +++ + + CG 118 + + ++ + + CG 119 ++ ++ +++ +++ ++ CG 120 ++++ ++++ ++ ++++ CG 121 +++++ +++++ ++++ ++++ ++++ CG 122 ++++ ++++ ++ ++ ++ CG 123+++++ ++++ ++++ ++++ ++++ CG 124 +++++ +++++ ++++ ++++ ++++ CG 125 ++++++++ ++++ ++++ ++++ CG 126 ++++ ++++ ++++ ++++ +++ CG 127 +++++ ++++++++ ++++ ++++ CG 128 ++++ ++++ ++++ ++++ ++++ CG 129 +++ +++ +++ ++++++ CG 130 ++++ ++++ ++++ ++++ ++++ CG 131 +++++ +++++ ++++ ++++ ++++ CG132 +++++ +++++ +++++ +++ +++ CG 133 +++++ +++++ +++++ +++++ +++++ CG134 +++++ +++++ ++++ ++++ ++++ CG 135 +++++ +++++ ++++ ++++ ++++ CG 136+++++ +++++ ++++ ++++ ++++ CG 137 +++++ +++++ +++ +++ +++ CG 138 ++++++++++ +++ ++ +++ CG 139 +++++ +++++ ++ + +++ CG 140 +++++ +++++ ++++++++ ++++ CG 141 +++++ +++++ ++++ ++++ ++++ CG 142 ++++ ++++ ++++ ++++++++ CG 143 +++++ +++++ +++++ +++++ +++++ CG 144 +++++ +++++ +++++ ++++++++++

Example 30 Release of Cannabinoid from Extruded Chewing Gum

TABLE 2B Chewing gum samples from Example 14 was tested for releaseafter 3 or 5 minutes of in vivo chewing according to the test method ofExample 24. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG100 CG101 CG102 CG103 CG104 3minutes 12 11 12 8 7 5 minutes 17 16 17 12 11

TABLE 2C Chewing gum samples from Example 15 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG100 CG101 CG102 CG103 CG104 3minutes 13 12 14 7 6 5 minutes 15 14 16 11 10

The result shows that in the outer end of the ranges according to theinvention, the release was lower, but still acceptable (CG103 andCG104). However, the ranges should be seen combined, such that the rangeof each of elastomer plasticizers and natural resin contributes incombination to the overall effect and release properties of the chewinggum. Hence, if an amount in the end of the range for natural resin isapplied, the amount of elastomer plasticizer may to some extendcounteract the negative effect.

Example 31 Release of Cannabinoid from Extruded Chewing Gum

TABLE 2D Chewing gum samples from Example 15 was tested for releaseafter 3 or 5 minutes of in vivo chewing according to the test method ofExample 24. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG105 CG106 CG107 CG108 CG109 3minutes 12 11 11 8 7 5 minutes 17 15 17 13 12

Table 2D: Chewing gum samples from Example 15 was tested for releaseafter 3 or 5 minutes of in vivo chewing according to the test method ofExample 24. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG).

TABLE 2E Chewing gum samples from Example 16 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG105 CG106 CG107 CG108 CG109 3minutes 13 11 14 7 6 5 minutes 15 13 16 12 11

The result shows that in the outer end of the ranges according to theinvention, the release was lower, but still acceptable (CG108 andCG109). However, the ranges should be seen combined, such that the rangeof each of elastomer plasticizers and natural resin contributes incombination to the overall effect and release properties of the chewinggum. Hence, if an amount in the end of the range for natural resin isapplied, the amount of elastomer plasticizer may to some extendcounteract the negative effect.

The release of CG 110-114 was comparable to CG105-109.

Example 32 Release of Cannabinoid from Extruded Chewing Gum

TABLE 2F Chewing gum samples from Example 17 was tested for releaseafter 3 or 5 minutes of in vivo chewing according to the test method ofExample 24. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG115 CG116 CG117 CG118 CG119 3minutes 12 11 6 4 7 5 minutes 17 16 7 6 9

TABLE 2G Chewing gum samples from Example 17 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG115 CG116 CG117 CG118 CG119 3minutes 13 12 3 2 6 5 minutes 15 14 6 5 8

The result is clear in the sense that addition of VA-VL to thecomposition provides a much lower release (CG 117-119) than by the useof the polymers and natural resin according to the present invention. Inaddition, the sensory properties by the use of VA-VL (see above) alsomakes it clear that VA-VL is not preferred.

Example 33 Release of Cannabinoid from Extruded Chewing Gum

TABLE 2H Chewing gum samples from Example 18 was tested for releaseafter 3 or 5 minutes of in vivo chewing according to the test method ofExample 24. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG120 CG121 CG122 CG123 CG124 3minutes 7 12 6 10 11 5 minutes 8 17 8 12 16

TABLE 2I Chewing gum samples from Example 18 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG120 CG121 CG122 CG123 CG124 3minutes 6 13 7 10 12 5 minutes 7 15 8 11 14

The addition of talc to the composition was expected to give a higherrelease of CBD since it was expected that talc would provide a moreporous structure to the extruded chewing gum and thereby promote betterrelease of CBD. However, this was not seen (CG120 and CG122) and itappears that the amount of sugar alcohols is more important for releasecharacteristics than previously expected.

Example 34 Release of Cannabinoid from Extruded Chewing Gum

TABLE 2J Chewing gum samples from Example 19 was tested for releaseafter 3 or 5 minutes of in vivo chewing according to the test method ofExample 24. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG125 CG126 CG127 CG128 CG129 3minutes 7 11 12 14 18 5 minutes 8 13 17 19 22

TABLE 2K Chewing gum samples from Example 19 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG125 CG126 CG127 CG128 CG129 3minutes 6 10 13 15 17 5 minutes 7 12 14 16 21

The results shows that a too low amount of sugar alcohol in the gum(CG125) caused problems with the release of cannabinoids and that ahigher amount was desirable. Overall, this was a surprise. However, atoo high amount of sugar alcohol (CG129) affected other properties ofthe chewing gum as seen in the sensory results which was not expected.

Example 35 Release of Cannabinoid from Extruded Chewing Gum

TABLE 2L Chewing gum samples from Example 20 was tested for releaseafter 3 or 5 minutes of in vivo chewing according to the test method ofExample 24. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG130 CG131 CG132 CG133 CG134 3minutes 19 12 8 18 11 5 minutes 23 17 11 22 16

TABLE 2M Chewing gum samples from Example 20 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG130 CG131 CG132 CG133 CG134 3minutes 18 13 7 17 12 5 minutes 22 15 10 21 14

The result shows that CBD 10% (CG130 and CG133) contributes with ahigher release from the extruded chewing gum than CBD 52% (CG130 andCG134). This result is very surprising and appears to be a general trendthat has not previously been recognized. Addition of an isolate (CG 132)resulted in a little lower release from the gum, but still acceptable.It appears unknown why the release differs as seen. This result may beused to specifically design a controlled release profile ofcannabinoids. A certain amount of for instance CBD 52% together with acertain amount of CBD 10% makes it possible to design the release ofCBD, given that the release profiles are different.

Example 36 Release of Cannabinoid from Extruded Chewing Gum

TABLE 2N Chewing gum samples from Example 21 was tested for releaseafter 3 or 5 minutes of in vivo chewing according to the test method ofExample 24. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG135 CG136 CG137 CG138 CG139 3minutes 11 12 11 12 14 5 minutes 16 17 18 19 20

Generally, a slightly higher release of CBD was obtained with a higheramount of high-intensity sweetener in the extruded chewing gumformulation. This was highly unexpected since the amount ofhigh-intensity sweetener is relatively low in the extruded chewing gum.However, as seen in the sensory test above, when the amount ofhigh-intensity sweetener is in the high end (such as CG139), it mayimpact other properties of the extruded chewing gum.

Example 37 Release of Cannabinoid from Extruded Chewing Gum

TABLE 2L Chewing gum samples from Example 22 was tested for releaseafter 3 or 5 minutes of in vivo chewing according to the test method ofExample 24. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG140 CG141 CG142 CG143 CG144 3minutes 11 5 8 15 18 5 minutes 16 7 10 18 22

TABLE 2M Chewing gum samples from Example 22 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG140 CG141 CG142 CG143 CG144 3minutes 12 6 9 14 20 5 minutes 14 7 10 17 25

The overall result shows that release promoting systems, such as acyclodextrin complex with CBD (CG143) or self-emulsifiers systems(CG144), may be a particular advantage according to the invention if ahigher release is desirable. However, the use of microcrystallinecellulose as a carrier in a 10% MCC-system (CG142) did provide a loweroverall release which was even lower for a 5% MCC-system (CG141).

Example 38 Stability Test

TABLE 2N Chewing gum sample CG132 was tested under extreme conditions,60° C./4% RH in accordance with Example 26. In this example, CBD waspresent as CBD isolate in accordance with Example 8. Sorbitol wassubstituted with isomalt in CG132. CBD THC LC LC CG132 (mg/piece) % LC(mg/piece) % LC  0 months 5 96 0 0 14 days 5 94 0 0  1 month 5 84 0 0  3months 5 56 0 0

In comparative studies for other delivery vehicles, it has been seenthat CBD degrades to THC and later to CBN under extreme conditions.However, the results of this study shows that CBD was not degraded toTHC or later to CBN when extruded chewing gum was used as the deliveryvehicle. This was highly surprising and indicates that CBD is betterprotected in an extruded chewing gum matrix.

Example 39 Preparation of Cannabinoid Chewing Gum Formulation withSpecific Order

The time of addition of CBD 52% according to Example 13 was changed inthis Example. While the time of addition was 8 minutes in Examples 13,the following additional time table was prepared in order to reveal thesubstantive meaning of the time of addition on the release ofcannabinoids:

TABLE 3A It was secured that CBD was thoroughly mixed into thecomposition and that a homogeneous mixture was obtained. Sugar alcohol*was prepared as a premix with CBD according to Example 9. Here, thecontent in weight % is calculated as the sugar alcohol content,excluding the CBD content in the premix. CBD 52%* was prepared accordingto Example 6. The chewing gum composition was abbreviated CG100 (Example14). Specified order of addition in the preparation of chewing gum(CG100) Application time in Ingredient Content in weight % min. CBD 52%*1 0 CBD 52%* 1 3 CBD 52%* 1 5 CBD 52%* 1 8 CBD 52%* 1 12 Total 13

Example 40 Release of Cannabinoid from Extruded Chewing Gum

TABLE 3B Chewing gum samples from Example 14 (CG100) was tested forrelease of CBD after 5 minutes of in vivo chewing according to thespecification of Example 13. The test method of Example 24 was applied.The value indicates weight % of cannabinoid released from the chewinggum sample (CG). Application time in min. Release % 0 7 3 9 5 10 8 14 1215

The result shows that release of the one or more cannabinoids may bedependent on the application order during the manufacturing process ofextruded chewing gum. In this example, it was seen that application ofthe one or more cannabinoids after half the mixing time was favorable,just as long as the cannabinoids were homogeneously distributed in theextruded gum. The application time of 8 minutes in this example or evenlater was particularly favorable.

Example 41 Coating with CBD

TABLE 3C Chewing gum samples from Example 23 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG145 CG146 3 minutes 60 55 5minutes 59 61

The result was highly surprising since it was expected that a majoramount of CBD from the coating was absorbed in the chewing gum uponchewing. However, the result shows that application of one or morecannabinoids into a coating, such as a hard coating, may be a promisingway to deliver cannabinoids. Also, by combining the application of oneor more cannabinoids in the coating as well as in the extruded chewinggum, controlled release of cannabinoids may be obtained. This may alsobe used to provide a biphasic release of cannabinoids, such that aninitial high release is provided by the coating and a more sustainedrelease is provided by incorporating the cannabinoids in the extrudedchewing gum.

Example 42 CBD Delivered to the Oral Mucosa

Tests were conducted in accordance with the test method of Example 27.The tests were performed for CG100 and CG101. The values for the CBDcontent in saliva and in the chewing gum residue were measured after 5min of chewing. From these values, the content of CBD delivered to theoral mucosa could be calculated.

TABLE 3D Chewing gum samples from Example 14 were tested for content ofCBD delivered to the oral mucosa after 5 minutes of in vivo chewingaccording to the test method of Example 27. The values indicate weight %of cannabinoid based on the one or more cannabinoids present in theinitial formulation. CG Number CG100 CG101 CBD in saliva 0.1 0.1 CBD inresidue 87 88 CBD delivered to 12.9 11.9 mucosa

The results of the tests were very surprising as almost all CBD releasedafter 5 minutes of chewing was delivered to the oral mucosa. It wasexpected that a much higher amount of CBD was present in the salivaafter 5 minutes of chewing, but only a very low amount of CBD was foundin the saliva. Based on the released amount of CBD (13% respective 12%),it could be calculated that <1% of the released CBD was present in thesaliva and accordingly >99% CBD was delivered to the oral mucosa. Hence,the chewing gum formulation of the invention is very suitable fordelivery of cannabinoids to the oral mucosa, much better than would havebeen expected.

Example 43 CBD Delivered to the Oral Mucosa

Tests were conducted in accordance with the test method of Example 27.The tests were performed for CG145 and CG146. The values for the CBDcontent in saliva and in the chewing gum residue were measured after 5min of chewing. From these values, the content of CBD delivered to theoral mucosa could be calculated.

TABLE 3E Chewing gum samples from Example 23 were tested for content ofCBD delivered to the oral mucosa after 5 minutes of in vivo chewingaccording to the test method of Example 27. The values indicate weight %of cannabinoid based on the one or more cannabinoids present in theinitial formulation. CG Number CG145 CG146 CBD in saliva 35 35 CBD inresidue 40 45 CBD delivered to 25 30 mucosa

The results of the tests were surprising as a very high amount of CBDreleased after 5 minutes of chewing was delivered to the oral mucosa. Itwas expected that a much higher amount of CBD was present in the salivaafter 5 minutes of chewing. The total content of CBD delivered to theoral mucosa could be calculated to be about the double of the totalcontent of CBD delivered to the oral mucosa when CBD was present in thechewing gum (Example 42) compared to the coating (Example 43). It wasnot expected that such a high content of CBD could be delivered to theoral mucosa with the present chewing gum formulation. In fact, thecontent of CBD would be higher if polysorbate was not applied in thecoating suspension since polysorbate facilitates emulsifying propertiesof the saliva which prevent CBD to be delivered to the oral mucosa to aneven higher degree.

By varying the content of CBD in the coating and the content of CBD inthe chewing gum, a controlled delivery system may be established.

What is claimed is:
 1. A cannabinoid chewing gum with improved flavorperception, the cannabinoid chewing gum comprising water-soluble chewinggum ingredients and water-insoluble gum base, wherein the cannabinoidchewing gum comprises one or more cannabinoids that forms part of anextract having a content of at least 10% by weight of unboundcannabinoids with an off-note taste and a content of terpenes andflavonoids, wherein the cannabinoid chewing gum comprises one or morehigh intensity sweeteners in an amount of 0.05 to 0.9% by weight of thecannabinoid chewing gum that partly serves to mask the taste of saidunbound cannabinoids, wherein the cannabinoid chewing gum comprises oneor more flavoring ingredients in an amount of 0.01 to 5% by weight ofthe cannabinoid chewing gum that in combination with the one or morehigh intensity sweeteners partly serves to mask the taste of saidunbound cannabinoids, wherein the one or more cannabinoids is located inclose proximity with the one or more high intensity sweeteners as wellas the one or more flavoring ingredients.
 2. The cannabinoid chewing gumaccording to claim 1, wherein at least 90% by weight of the one or morecannabinoids is present in unbound form.
 3. The cannabinoid chewing gumaccording to claim 1, wherein the one or more high intensity sweetenersis part of the water-soluble chewing gum ingredients.
 4. The cannabinoidchewing gum according to claim 1, wherein the one or more flavoringingredients is part of the water-soluble chewing gum ingredients.
 5. Thecannabinoid chewing gum according to claim 1, wherein the water-solublechewing gum ingredients and water-insoluble gum base are partlyseparated in the cannabinoid chewing gum.
 6. The cannabinoid chewing gumaccording to claim 1, wherein the water-soluble chewing gum ingredientsare partly located in one layer of the cannabinoid chewing gum and thewater-insoluble gum base is located in another layer of the cannabinoidchewing gum.
 7. The cannabinoid chewing gum according to claim 1,wherein the water-soluble chewing gum ingredients are partly located inone layer of the cannabinoid chewing gum together with the one or morecannabinoids, the one or more high-intensity sweetener, and the one ormore flavors
 8. The cannabinoid chewing gum according to claim 1,wherein the water-insoluble gum base is not located in a layercomprising the one or more cannabinoids.
 9. The cannabinoid chewing gumaccording to claim 1, wherein the release rate of the one or more highintensity sweeteners is about the same as the release rate of the one ormore cannabinoids upon oral administration.
 10. The cannabinoid chewinggum according to claim 1, wherein the release rate of the one or moreflavoring ingredients is about the same as the release rate of the oneor more cannabinoids upon oral administration.
 11. The cannabinoidchewing gum according to claim 1, wherein the one or more cannabinoidsis selected from the group consisting of cannabidiol (CBD),cannabidiolic acid (CBDA), cannabidivarin (CBDV), and combinationsthereof.
 12. The cannabinoid chewing gum according to claim 1, whereinthe one or more cannabinoids is selected from the group consisting oftetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),tetrahydrocannabivarin (THCV), and combinations thereof.
 13. Thecannabinoid chewing gum according to claim 1, wherein the one or morecannabinoids comprises at least two cannabinoids.
 14. The cannabinoidchewing gum according to claim 1, wherein the one or more cannabinoidsis present in a premixture with one or more sugar alcohols orsaccharides.
 15. A cannabinoid chewing gum with improved flavorperception, the cannabinoid chewing gum comprising water-soluble chewinggum ingredients and water-insoluble gum base, wherein the cannabinoidchewing gum comprises one or more cannabinoids with an off-note taste incombination with one or more self-emulsifying agents that forms anemulsion upon release of the one or more cannabinoids when exposed to analternate phase with a minimum energy requirement, wherein thecannabinoid chewing gum comprises one or more high intensity sweetenersin an amount of 0.05 to 0.9% by weight of the cannabinoid chewing gumthat partly serves to mask the taste of said cannabinoids, wherein thecannabinoid chewing gum comprises one or more flavoring ingredients inan amount of 0.01 to 5% by weight of the cannabinoid chewing gum that incombination with the one or more high intensity sweeteners partly servesto mask the taste of said cannabinoids, wherein the one or morecannabinoids is located in close proximity with the one or more highintensity sweeteners as well as the one or more flavoring ingredients.16. The cannabinoid chewing gum according to claim 15, wherein the oneor more self-emulsifying agents is part of a self-emulsifying drugdelivery system (SEDDS) comprising oils and a surfactant.
 17. Acannabinoid chewing gum with improved flavor perception, the cannabinoidchewing gum comprising water-soluble chewing gum ingredients andwater-insoluble gum base, wherein the cannabinoid chewing gum comprisesone or more cannabinoids with an off-note taste and one or more lipidcarriers for the one or more cannabinoids, wherein the cannabinoidchewing gum comprises one or more high intensity sweeteners in an amountof 0.05 to 0.9% by weight of the cannabinoid chewing gum that partlyserves to mask the taste of said cannabinoids, wherein the cannabinoidchewing gum comprises one or more flavoring ingredients in an amount of0.01 to 5% by weight of the cannabinoid chewing gum that in combinationwith the one or more high intensity sweeteners partly serves to mask thetaste of said cannabinoids, wherein the one or more cannabinoids islocated in close proximity with the one or more high intensitysweeteners as well as the one or more flavoring ingredients.
 18. Thecannabinoid chewing gum according to claim 17, wherein the one or morelipid carriers for the one or more cannabinoids comprises an oilcarrier.
 19. A cannabinoid chewing gum with improved flavor perception,the cannabinoid chewing gum comprising water-soluble chewing gumingredients and water-insoluble gum base, wherein the cannabinoidchewing gum comprises one or more unbound cannabinoids with an off-notetaste, wherein the cannabinoid chewing gum comprises one or more highintensity sweeteners in an amount of 0.05 to 0.9% by weight of thecannabinoid chewing gum that partly serves to mask the taste of saidunbound cannabinoids, wherein the cannabinoid chewing gum comprises oneor more flavoring ingredients in an amount of 0.01 to 5% by weight ofthe cannabinoid chewing gum that in combination with the one or morehigh intensity sweeteners partly serves to mask the taste of saidunbound cannabinoids, wherein the release rate of the one or more highintensity sweeteners and the one or more flavoring ingredients is aboutthe same as the release rate of the one or more cannabinoids upon oraladministration.
 20. The cannabinoid chewing gum according to claim 19,wherein the release rate is at least 10% by weight within the first 5minutes upon oral administration.